Kimberly A Yonkers MD
Associate Professor of Psychiatry, Obstetrics and
Gynecology and Reproductive Sciences
Yale School of Medicine
New Haven, CT
USA

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Preface

Somatic, affective, and behavioral symptoms can occur
during the premenstrual phase of the menstrual cycle of
nearly all ovulatory women. The nature and severity of
these symptoms constitute a spectrum from minimal to
disabling; however, the distinction between normal and
pathological symptoms is one of the principal dilemmas in this area of research. The severity of interference
with daily activities depends on various as yet poorly
defined factors, but etiology probably includes genetic,
neurochemical, and environmental factors. Are we
really, in this era of high technology, limited to the use
of simple paper-based rating scales to record the impact
of symptoms on normal functioning, on school and
work performance, and on ability to socialize? Yes, at
present, this remains the most reliable way to distinguish between what is physiological and what constitutes a premenstrual disorder, premenstrual syndrome
(PMS) or premenstrual dysphoric disorder (PMDD).
Awareness of such premenstrual problems amongst
women, their partners, general practitioners, gynecologists, psychiatrists, other health professionals and, particularly, the media has increased dramatically over the
past 30 years.
Even so, there are sceptics who say that premenstrual
symptoms or disorders have been exaggerated and
medicalized by the profession and the pharmaceutical
industry, in order to ‘peddle’ their hormones (progestagens and estrogen) or antidepressants (notably selective
serotonin reuptake inhibitors, SSRIs). Complementary
and alternative practitioners have also offered a range
of treatments: some ineffective; others, poorly studied,
but possibly effective. Premenstrual symptoms, similar
to many affective and behavioral symptoms, exhibit a
very high response to placebo, and significant symptoms can occur in at least 20% of women. The lack of
consensus on the nature of this condition creates a void

of knowledge, in which some women may unfortunately become targets for exploitation. However, it is of
paramount importance that scientific research continues and that the medical community recognizes and
cares for these disorders. It would be a great disservice
to women and society if those in the medical community (who have insufficient knowledge and understanding) approach these problems with disdain.
Premenstrual syndrome is amongst a unique, small
number of disorders where the patient frequently
arrives at the specialist with their own diagnosis and it
is the practitioner’s role to exclude or confirm the diagnosis. The lack of an objective means of confirming the
diagnosis and monitoring treatment is a great problem.
This may be one of the reasons why the credibility of
the diagnosis of PMS has been questioned. Although
this is probably true for other psychological disorders,
it is probably more so for PMS.
In the USA and in Australasia, PMS is recognized
as a serious entity, but in the UK and continental
Europe less so. The National Institute of Mental Health
(NIMH) in Washington, DC, the American Psychiatric
Association, and the American College of Obstetricians
and Gynecologists (ACOG) respect the validity of these
disorders in that research program grants, evidencebased clinician guidance, and patient information are
well-established and widely disseminated. By contrast,
in the UK, all PMS/PMDD research has been led by the
pharmaceutical industry and only now, for the first
time, is the Royal College of Obstetricians and Gynaecologists developing evidence-based guidance for treatment. The situation in the rest of Europe probably falls
somewhere between these two extremes. A patient/consumer group in the UK, The National Association of
Premenstrual Syndrome, has been the focus of activity
in the field and has a relatively scientific view of most

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xii PREFACE

matters relating to PMS. In the UK and rest of Europe,
the only licensed preparations for managing PMS are
progesterone and various progestins, yet we will see in
the following chapters that there is incontrovertible evidence that these are ineffective. Many other effective
but unlicensed approaches are used in the UK and
Europe: we have a situation where everything that is
licensed is ineffective and everything that works is unlicensed! By contrast, in the USA, Canada, and
Australasia, both the SSRI class of drugs as well as a
novel oral contraceptive pill (for women who also want
hormonal contraception), are licensed and prescribed
extensively with guidelines for psychiatrists and gynecologists (ACOG) recommending either SSRIs or the
newer drospirenone-containing oral contraceptive pill
as first-line therapies for severe PMS or PMDD.
Clinical and basic science researchers in wide-ranging
fields of study, including gynecology, psychology, psychiatry, endocrinology, genetics, brain imaging, and
neurophysiology, have been interested in the exploration of this disorder for over 70 years, with an escalation of interest around the mid 1970s until today.
This is the first multi-author textbook of its kind to
focus solely on the premenstrual disorders of PMS and
PMDD. Contributions have been received from individuals from most the units in Europe and the USA
who have extensively researched and treated premenstrual tension, PMS, and PMDD.
The three editors have been involved in research into
PMS for decades. They comprise a UK professor of
obstetrics and gynecology from Keele University
(PMSOB) who is currently also vice president of the
Royal College of Obstetricians and Gynaecologists; a
research and clinical psychiatrist from the NIMH in
Washington, DC (PJS), and a well-established professor
of obstetrics and gynecology from UCLA (AJR).
When setting about this book, we decided to choose
authors who could represent virtually every major unit
actively investigating aspects of PMS and PMDD in the
UK, continental Europe, and the USA. It is hoped that
no subject area has been left uncovered and no research
group from these geographical areas overlooked.
Within the book there will be areas that are repeated
or are contradictory, as views differ and it was felt inappropriate to edit out these views simply to be uniform.
The reader will be able to appreciate ideological
contrast and differing perceptions and experiences
between psychiatrists and gynecologists, Europeans
and Americans, clinicians and basic scientists, geneticists

and endocrinologists. There is also, not surprisingly,
agreement and disagreement within members of the
same specialist areas. This adds to the richness of the
debate and gives a fuller understanding of the current
landscape. They are very much chapters written as the
individuals see the issues, and often the emphasis will
differ markedly. For instance, few authors from the
USA contemplate giving estrogen, even though the evidence would support it. Few US authors would contemplate surgery. In the UK, there are strong advocates
of ovulation suppression with transcutaneous estrogen
therapy and, though only rarely and in severely affected
patients, UK clinicians would be more willing to offer a
surgical option – meaning, of course, the curative but
very invasive decision to allow patients who request
surgery to undergo hysterectomy and bilateral salpingooophorectomy. The research on this dramatic approach, however, has come from Canada and the USA as
well as from the UK.
US psychiatrists, particularly, favor the use of the
term PMDD and the use of SSRIs in management. The
oral contraceptive pill is more readily advocated by US
gynecologists, whereas the use of the levonorgestrel
intrauterine system (LNG IUS, Mirena) is used extensively by UK gynecologists, not as a primary treatment
method but to protect the endometrium from estrogeninduced hyperplasia during ovulation suppression
using transcutaneous estrogen therapy. The use of psychotropic therapy and, more specifically, the SSRIs has
been led by US and Canadian psychiatrists and Swedish
researchers.
I think it is true to say that the study and publication
of work on SSRI therapy predated any serious understanding of the neurobiology of PMS/PMDD, but this
is now such a fascinating area that involves animal
research, biochemical study, brain imaging with functional magnetic resonance imaging (fMRI) and positron
emission tomography (PET) scanning, and finally
genetics. This combination of research, which is all
being currently undertaken, will give us the best chance
of succeeding in reaching a valid explanation for the
etiology and then the cure of the premenstrual disorders within the early part of the 21st century.
The science of the premenstrual disorders and, hopefully, this textbook should stimulate and whet the
appetite of anyone who has not already embarked on
the investigation of this area.
PMSO

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1
History of the premenstrual disorders
PM Shaughn O’Brien and Khaled MK Ismail

INTRODUCTION
The study of premenstrual syndrome (PMS) appears to
have been full of contradictions over many decades.
However, progress in understanding the etiology and
providing therapy for this condition has accelerated in
recent years.
The easiest and most appropriate way to describe the
history of the premenstrual disorders is to divide it into
four eras based on the historical changes in terminology
used in the literature. These four landmark stages parallel our understanding of the premenstrual disorders.
The eras are:

●

●

●

●

From the ‘agitations’ of Hippocrates (370 BC) to
premenstrual tension (PMT);1 in this period, the
recognition and description of symptoms were first
realized and the beginnings of an understanding of
the problem began.
From PMT to PMS;2 in this period, the link between
the ovarian hormone cycles and symptoms was
recognized.
From PMS to the American Psychiatric Association’s definition of premenstrual dysphoric disorder
(PMDD) (via late luteal phase dysphoric disorder
[LLPDD]); in this period, a great deal of scientific
energy was expended in an attempt to define and
quantify premenstrual disorders and the theory of
progesterone deficiency was explored and refuted.
From PMDD to the present day; in this period there
has been the realization that women are sensitive to
normal levels of ovulatory progesterone, that this
possibly has a neuroendocrine explanation, and that
therapy can be achieved by altering neuroendocrine
status with psychotropic drugs (notably selective
serotonin reuptake inhibitors [SSRIs]) or by elimination of ovulation.

FROM HIPPOCRATES’ ‘AGITATIONS’
TO FRANK’S PMT
Much is written in historical and religious texts regarding menstruation. There seems to be a strong need to
claim that premenstrual symptoms were first described
in the Torah, the Talmud, or the works of Hippocrates.
Although there is extensive discussion and teaching
related to menstruation in the two religious works, it is
difficult to find anything that can be directly considered
to describe premenstrual symptoms before the works
attributed to Hippocrates. Much was written in myth
related to menstruation and behavior, but one cannot
clearly distinguish what does and what does not refer to
the menstrual, pre-, or perimenstrual time phase associations with mood and behavior. What was written originally (often in Greek mythology) tended to be positive
about menstruation, but as time progressed this became
more negative. There are, however, several instances in
Hippocrates’ works where there are statements or aphorisms which clearly describe premenstrual symptoms:
The blood of females is subject to intermittent
‘agitations’ and as a result the ‘agitated blood’
makes its way from the head to the uterus whence
it is expelled.3
Women experience a feeling of heaviness prior to
menstruation.4
Beyond Hippocrates, many years passed before the
literature identifies further reference to premenstrual
symptoms. Halbreich5 cites three important descriptions of severe premenstrual symptoms.
The first of these was by an 11th century female
Italian scholar, Trotulo of Salerno, who wrote:
There are young women who suffer in the same
manner, who are relieved when their menses are
called forth.

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2 THE PREMENSTRUAL SYNDROMES

The second was also Italian; Giovani da Padua in the
16th century described fairly clearly a link between
menstruation and depression.
Finally, Halbreich quotes the English physician James
Cowles Prichard, who wrote:
Some females at the period of the catamenia
undergo a considerable degree of nervous excitement, morbid dispositions of mind are displayed
by them at these times, a wayward and capricious
temper, excitability in the feelings, moroseness in
disposition, a proneness to quarrel with their
dearest relatives and sometimes a dejection of
mind approaching to melancholia.
What could be closer to this as a description of PMS,
published in 1837?6
Ian Brockington’s work on menstrual psychosis7 is
another valuable source of historical information. In it,
he quotes the works of JE Hitzig, Briere de Boismont,
and Richard von Krafft-Ebing.
In 1828, Hitzig described menstrual mood disorder
in relation to an acquittal for filicide. Having been condemned to death for drowning her child, a mother
confided in a fellow prisoner that she experienced inexplicable symptoms before and during her period. Following medical observation of this and various physical
phenomena, she was acquitted.
Briere de Boismont described four cases of premenstrual psychosis and described the relationship between
menstruation and surexcitation or overstimulation and
agitation:
Surexcitation: 8 synonymes: agitation, bouillonnement, délire, ébullition, échauffement, effervescence, exaltation, fièvre.
Brockington quotes frequently the seminal work of
Richard von Krafft-Ebing,8 in which he described 60
cases of menstrual psychosis.

FROM PMT TO DALTON’S PMS:
PREMENSTRUAL TENSION
Robert Tilden Frank (1875–1949)1 was a New York
gynecologist who graduated from Harvard and subsequently worked in Columbia University and as chief of
the gynecological service at Mount Sinai Hospital in
New York. In 1931 he described for the first time the
condition premenstrual tension in a paper read at the
Academy of Medicine, New York:
My attention has been increasingly directed to a
large group of women who are handicapped by
premenstrual disturbances of a manifold nature.

It is well known that normal women suffer varying
degrees of discomfort preceding the onset of menstruation. Employers of labour take cognisance of
this fact and make provision for the temporary
increased fatigability, irritability, lack of concentration and attacks of pain. In another group of
patients the symptoms complained of are of sufficient gravity to require rest in bed for one or
two days. In this group particularly, pain plays a
prominent role. There is still another class of
patients in whom grave systemic disorders manifest themselves predominantly during the premenstrual period.
Frank suggested initially that an excess of ovarian
estrogen (due to diminished excretion) was the underlying cause, and he went on to illustrate this with cases –
some of which were treated by irradiation of the
ovaries, presumably resulting in a radiation menopause.
Jeliffe (1906) had hinted at this previously in a report in
the New York State Journal of Medicine (cited in
Halbreich),5 but it was Frank who brought the subject
and its probable link with the ovarian cycle to the
attention of the medical world. Frank clearly was the
first to describe premenstrual tension but, at the same
time, Karen Horney, a German psychoanalyst who
moved to the USA in the early 1930s, described (independently from Frank) ‘Die pramenstruellen Verstimmungen’ in 1931.9 She highlighted the disappearance
of symptoms with the onset of menstruation and its
recurrent nature. She attributed the symptoms to estrogenic hormone from the ovary but recognized that this
was related to the corpus luteum.
Between Frank’s publication and the writings of
Katherina Dalton in 1953, many theories were developed
and proposed for the etiology, including antidiuretic
hormone, hormone allergy, deficiency of various vitamins and minerals (including potassium, calcium, and
magnesium), hypoglycemia/insulin excess, estrogen/
progesterone imbalance, pelvic congestion, ‘menotoxin’,
progesterone deficiency, and salt and water retention,
and of course there were many purely psychological
theories. It is not appropriate to discuss every one of
these: those that are important are discussed in other
chapters of this book, whereas those which are less
important can be found in the editor’s (P.M.S.O.) earlier
textbook, Premenstrual Syndrome.10

FROM PMS TO THE AMERICAN
PSYCHIATRIC ASSOCIATION’S PMDD
In 1950, Morton was first to advocate the (subsequently disproved) theory of progesterone deficiency

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HISTORY OF THE PREMENSTRUAL DISORDERS 3

and estrogen/progesterone imbalance. Dalton2 took
this theory, and the claim that ‘pure’ progesterone would
provide treatment, to a high level of consciousness internationally in the medical, lay, and political world. She
coined the new term premenstrual syndrome (PMS) and
this is the term still largely used throughout the world
by the majority of women and most physicians, general
practitioners, gynecologists, and (with the exception of
North America), most psychiatrists.
Dalton must be credited for bringing this syndrome
to the attention of the medical world, as without her
crusading intervention the problem of PMS may well
have been ignored. Her blind support for progesterone
therapy in the face of the evidence of its inefficacy was
unscientific but of course she was practicing and her
views did stem from the early 1950s.
Katherina Dalton was a charismatic general practitioner in London. As a medical student, she suffered
severe menstrual migraine that disappeared during
her four pregnancies. She put two and two together,
and, with the endocrinologist Dr Raymond Greene,*
embarked on a personal exploration of progesterone
therapy. Katherina Dalton became free from premenstrual migraines by administration of daily injections of
progesterone from ovulation to menstruation. Accordingly, and not surprisingly, her enthusiasm and dedication grew from here on and she went on in the 1950s
and 1960s to report subsequently on a series of anecdotal cases of successful treatment of premenstrual
asthma, eczema and migraines in her patients.
Between the time of Dalton’s early descriptions of
PMS and the era which led to more precise diagnosis and
measurement, many theories were proposed and much
research was undertaken. Many of these efforts led to
today’s research, but it must be admitted that much of
what we know from that era was based on diagnostic
criteria that were imprecise and thus limited lasting
conclusions can be drawn from much of that work.
The dominant theories and work focused on several
areas over the time span of 1953 to the late 1980s
(Table 1.1). These areas were:
●

Ovarian endocrine research dominated this era. Research
focused on estrogen and, particularly, progesterone,
arising from Dalton’s progesterone deficiency crusade.
By the end of this historical phase it became clear that
research had produced studies demonstrating high,
low, or no differences in progesterone or estrogen levels
in PMS patients compared with controls. Researchers,
and, more so, the pharmaceutical industry, selected
those data that supported their case. The case for progesterone deficiency was more or less dispelled but this
did not stop the continued prescription of, and indeed
licensing of, progesterone by several routes and progestogens orally. It is of interest to note that in the UK these
preparations continue to be the only preparations
licensed for PMS and so they are widely prescribed
in the face of overwhelming evidence that they are
ineffective.
Although some studies did demonstrate differences
to support these theories, it must be realized that few
were replicated and probably what is more important is
that the specific criteria and quantification techniques
used now were not available. Reliance cannot be made
on supportive or negative findings for most of these
studies.
Where these findings are relevant to today’s practice
and research they will be addressed in the individual
chapters which follow. More detailed reference can
again be found in O’Brien’s Premenstrual Syndrome
(1987), which covers the available research up to that
year.91

Therapy
In the era from 1950 to the late 1980s and early 1990s,
treatment research moved from anecdotal reporting of
cases through non-blind trials to well-controlled randomized double-blind trials. However, meta-analysis
had not yet made any impact in this sphere of research.
The area of these studies matched that of the studies of
etiology to a large extent. The number of therapeutic
studies conducted during that time period was huge, as
the existence of PMS had reached public consciousness –
everything available was being used to treat PMS. With
such a large initial placebo response and the existence
of many patients labeled as PMS who had much milder
problems, the pharmaceutical industry and complementary and alternative therapy companies were having
a field day.
Again, it is not appropriate to list every study: details
will again be found in the individual chapters of this
book or in O’Brien’s book.1
Table 1.2 aims to summarize the different treatments
which had been proposed or researched. The list is not
intended to be exhaustive but gives a flavor of the range
and number of therapies proposed during the era.

Most early studies relied on the patient’s perception of
her symptoms or the clinician’s diagnosis from history
and observation alone. Through this time period, a great
deal of work was conducted aiming to define PMS more
precisely and to devise methods to measure symptoms.
The first method dedicated specifically to menstrual
or premenstrual symptoms was the Moos, Menstrual
Distress Questionnaire.11 This was a rating scale which
used a 47-symptom six-point rating scale. Subsequent
new scales followed this template, which used different
combinations of symptom types; scores which ranged
from 0 to 3, 4, 5, 6, and 7. In the same era, the first use
of a visual analog scale (VAS) was published (1979)
and, much later, improvements led to VAS charts that
adhered to the criteria required for PMDD.
Definitions and diagnostic criteria also evolved over
this time period. Having begun with Frank’s PMT and

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HISTORY OF THE PREMENSTRUAL DISORDERS 5

Dalton’s PMS, new, more precise terms were developed.
In 1987, the terminology and criteria for late luteal phase
dysphoric disorder (LLPDD) for the Diagnostic and
Statistical Manual of Mental Disorders, third edition
(DSM-III) of the American Psychiatric Association were
published. This is only now of historical interest, as the
later definition and criteria of premenstrual dysphoric
disorder, which was defined in DSM-IV,12 has replaced
it. In 1990 the Daily Record of Severity of Problems
(DRSP) provided a categorical rating (0–6) scale of all
of the symptom components required for PMDD.13,14
This was an important milestone in the evolution of
the science of premenstrual disorders. It provided clearcut guidance and criteria, but unfortunately with some
important limitations: e.g. the need for five symptom
groups excludes many patients with a severe premenstrual disorder but with fewer symptoms. Additionally,
it also confines the range of physical symptoms to a
single category, virtually excluding the diagnosis of
PMDD in a patient with predominantly physical symptoms. Cynics have been heard to say that this was intentional in order to exclude gynecology and to strengthen
the case for psychotropic therapy – particularly the
(then) newly emerging SSRIs.

FROM PMDD TO THE PRESENT
DAY AND BEYOND
The key events following the introduction of the concept
of PMDD represent the journey to our current understanding of all premenstrual disorders. This understanding will provide a real chance of determining a full
explanation of the mechanisms of premenstrual disorders (and subsequently their treatment) in the early part
of this century.

Developments in treatment approach
over the past 20 years
Given that current treatment offers the ability either to
suppress ovulation or to rectify an unknown neural biochemical derangement, we will again consider developments under these headings and with a causal theory/
treatment modality pairing.

Therapeutic research
In this era, hormonal therapy, cognitive behavioral
therapy, and psychotropic therapy became all-important:
in particular, transdermal estrogen, new combined contraceptive pills with novel progestogens (such as
drospirenone), and gonadotropin-releasing hormone

(GnRH) analogues (with and without add-back) became
serious contenders. The levonorgestrel IUS (intrauterine
system) was also introduced, first as a contraceptive
technique, then as a treatment for menorrhagia, and
next as the progestogenic component of hormone
replacement therapy (HRT). In the clinical arena, many
were using it to protect the endometrium from hyperplasia during ovarian suppression with estrogen in the
management of PMS – the rationale being, parallel
with its use in HRT, that the endometrium would be
protected while systemic levels remained low, thus
avoiding restimulation of PMS symptoms. Meta-analysis was introduced as a new powerful method to
analyze several trials that were relatively underpowered
to draw conclusions from the single studies. Finally, a
whole new research direction assessing psychotropic
therapy, particularly the SSRIs, began.

Hormone therapy
Katherina Dalton’s theory of progesterone deficiency
and therapy using progesterone replacement was largely
dismissed during this time. It is an irony that her views
were the main stimulus to our interest in PMS in the
third quarter of the 20th century. For the same reasons,
the administration of oral progestogens was also considered valueless. This said, these two approaches remain
the only drugs prescribable under license in the UK for
PMS and, consequently, the most commonly prescribed
therapy in UK general practice.15
In the mid 1980s there was a transient enthusiasm for
theories related to prolactin excess and, thus, the use of
dopamine agonists. This enthusiasm waned after finding
that prolactin differences did not exist and that PMS
did not respond to bromocriptine therapy. It should
be mentioned that cyclical mastalgia does respond to
bromocriptine. Side effects can be problematic. It is
considered that late evening administration and lutealphase only treatment may minimize this, but there is no
confirmatory research. Bromocriptine therapy is thus
limited to PMS patients suffering with premenstrual
mastalgia.
Around the same time, similar views were being held
for the use of the androgenic preparation, danazol. There
was more evidence in favor of its positive benefit for
PMS symptoms (compared with bromocriptine) but the
doses required to suppress ovulation reliably were associated with the risk, or at least perceived risk, of side
effects, particularly masculinizing side effects. Luteal
phase administration of low-dose danazol was studied
and published with slightly conflicting findings. Certainly,
such a regimen was shown to be effective for cyclical
mastalgia (with minimal side effects)16 and one study
showed a beneficial effect on most PMS symptoms.17

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During the same era, there began an enthusiasm for the
use of evening primrose oil containing ␥-linolenic acid.
This was largely driven by the manufacturer and based
on quite spurious data. Again, though, breast symptoms appeared to be effectively relieved with minimal
side effects. Until quite recently there was a UK pharmaceutical license for mastalgia and, despite the lack of
supportive evidence of efficacy, relatively high doses
were available in ‘Premenstrual Packs’ as over-thecounter preparations in the high street pharmacy.
In the UK, a small group of clinical researchers had
always maintained a high degree of enthusiasm for
estrogen therapy, believing that such therapy should be
considered first line. John Studd, an eminent UK gynecologist, with his research group, had been as great an
advocate and enthusiast for estrogen therapy as
Katherina Dalton had been for progesterone. The difference, however, with Studd’s work was that:
●

●

the therapeutic approach was based on a realistic
theory; i.e. suppression of ovulation was achievable
using transdermal estrogen
he published well-controlled research to support the
efficacy of transdermal estrogen therapy.

Serotonin and SSRIs
Part of this historical research phase could reasonably
be known as the ‘serotonin phase’ of the science of
PMS. Research trials of SRIs/SSRIs (serotonin reuptake
inhibitors/selective serotonin reuptake inhibitors) had
begun as early as 1986 and had been reported soon
after. Beneficial effects had been shown, particularly for
fluoxetine, paroxetine, citalopram, sertraline, and venlafaxine. The Steiner et al19 fluoxetine paper was pivotal
in the approval of SSRIs by the US Food and Drug
Administration (FDA) and the UK Committee in Safety
of Medicines (CSM) licensing authorities, with longacting fluoxetine being recognized subsequently. The
UK and European license was lost when it was withdrawn by the European Medicines Agency (EMEA), the
European licensing agency, thus depriving a whole continent of the benefits of such treatment regimens. Fluoxetine is used off-license extensively for PMS, but this
advice is usually only given by the small number of
medical practitioners with specialized knowledge in the
area and, maybe, some well-informed general practitioners who choose to label the patients with this problem
as a variant of depression in order to justify its prescription. It is probably true to say that SSRIs are now
accepted as the first-line, non-hormonal therapy for PMS.
Some doctors would now consider them the first choice
in patients with severe PMS/PMDD. As a comment on
European intransigence to the licensing, it should also

be added that the acceptance of PMDD as an entity is
far from widespread.
Soon after the acceptance of SSRIs as treatment, there
began the realization that the actions of these drugs were
probably different from the mechanism found in its
antidepressant effect, to such an extent that luteal phase
dosing began and was shown to be effective in appropriately conducted trials. As the following chapters will
show, many researchers have been involved in the development and subsequent phases of this area of research,
which includes most SSRI work (see Chapter 15).
Systematic reviews are useful in establishing consistencies and significant variations in healthcare effects.
They are essential for the efficient integration of valid
information, and hence provide a basis for rational
decision-making.19 The use of explicit, systematic
methods in systematic reviews limits bias (systematic
errors) and reduces chance effects, thus providing more
robust results upon which to draw conclusions and
make decisions.20,21 Moreover, quality assessment of
individual studies included in a systematic review helps
to gain insight into potential comparisons and guides
interpretation of findings. Factors that warrant assessment are those related to applicability of findings,
validity of individual studies, and specific design characteristics that affect interpretation of results. ‘Metaanalysis’ is the term given to the process of using
statistical methods to summarize data of included independent studies. This collective analysis can provide
more precise estimates of the effects of health care than
those derived from the individual studies included in a
single review,22–24 thus facilitating decisions that are
based on the totality of the available evidence. With the
widespread acceptance of this methodology as the gold
standard for determining evidence-based management
in medicine, a series of systematic reviews were conducted to evaluate the effectiveness of therapeutic interventions used in PMS/PMDD.25–29 Meta-analysis is
now well-established internationally and benefits from
the visual presentation of collective data using Forest
Plots. The Cochrane database and library were the forerunners of this approach. The strength of meta-analysis
over uncontrolled trials, individual trials, unstructured
reviews, and even structured reviews should be noted.
The power of meta-analysis was realized, and analysis
of many therapeutic modalities was carried out in this
way for many medical areas, particularly for obstetrics
and menstrual disorders. The Cochrane Collaboration
led this approach to research.
For PMS/PMDD, meta-analyses were produced for
vitamin B6, progesterone, progestogens, GnRH analogues, GnRH analogues with add-back, and the SSRIs,
luteal phase SSRIs, and antidepressants, with danazol
and estrogen therapy to be published in the near future.

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HISTORY OF THE PREMENSTRUAL DISORDERS 7

Many other therapeutic areas have been covered in systematic views but not meta-analysis, which, as we have
said, represents the gold standard for clarity, power,
and precision.

Research into etiology
Much new work on estrogen, progesterone levels, suppression of the ovarian and cycle, and the investigation
of endocrine cycle paradigms became prominent (see
Chapter 10) during this era, led by the NIMH (National
Institute of Mental Health) group in Washington, DC,
and two groups in Sweden, at the Universities of
Gothenburg and Umea (see Chapters 3 and 13, respectively). This research was very much cause-driven, not
leading to an immediate therapeutic modality. Landmark
research was undertaken on hypotheses related to neuroanatomy, ovarian suppression with GnRH and restimulation paradigms, and neuronal biochemistry; this
work was particularly directed at serotonin and ␥aminobutyric acid (GABA) and conducted from the mid
1990s onwards.
Although no excess or deficiency in estrogen or progesterone levels has ever been demonstrated, the possibility of differences in progesterone receptors or
progesterone metabolites was considered by the UCLA
(University of California at Los Angeles) group (see
Chapter 9). Because of the affinity of allopregnanolone
for the GABA receptor and the lower measured levels
of allopregnanolone in PMS patients, it became a prominent recent theory of causation. It has not yet led to
specific treatment recommendations.
As it became clear that ovulation is the trigger for premenstrual events rather than differences in hormone
levels, attention became focused on the probability that
neural factors permitted an increased sensitivity to
ovarian steroids, particularly progesterone. Therapeutic
research on the SSRIs very convincingly demonstrated
a high level of efficacy, although it was realized that effective therapy does not automatically imply causality in
PMS (i.e. headache is not due to aspirin deficiency!). Effective SSRI treatment does not prove serotonin deficiency.
It is not surprising that research thereafter led to the
investigation of most neurotransmitters, including the
genetics of serotonin (5-hydroxytryptamine, 5-HT),
GABA, and PMS/PMDD. The editors of this book (and
several other groups) are currently investigating the
genetic basis of PMS and PMDD. Despite many differences being found in such disorders as depression,
seasonal affective disorder (SAD), and anxiety, the
exploration of polymorphisms in PMDD appeared initially unfruitful, although it now seems possible that
differences in polymorphisms for the 5-HT1A receptor
may be present compared with controls, and ultimately

these may show a linkage to cause and/or therapeutic
response (Vandana Dhingra, pers comm).
The inaccessibility of the brain makes the understanding of any psychological process or illness a major
challenge. If we analyze what has been available to investigators, our research tools are found to be sadly lacking.
Certainly, there is no objective test available to make a
diagnosis: peripheral blood tests need not necessarily
reflect central nervous system (CNS) levels or activity
(e.g. platelet and blood serotonin, ␤-endorphin); no
physical test has been identified; for measurements, we
are limited to patient-completed questionnaires; and
detailed psychiatric interviews have been available to
only a small number of studies.
The challenge of the complex inter-relationships seen
in neurological biochemistry and associated genetics is
made even more exciting by developments in brain
imaging. A greater understanding of this whole field is
poised to be unfolded by the arrival of techniques (see
Chapter 11) such as positron emission tomography
(PET), single-photon emission computed tomography
(SPET), and functional magnetic resonance imaging
(fMRI). These techniques offer a real chance of investigating and understanding brain function and blood flow,
which may link us to an understanding of premenstrual
disorders.

CONCLUSION
It has taken more than 20 centuries to move from
Hippocrates’ observation that women appeared to have
cerebral ‘agitations’ (which were released from the uterus
at menstruation) to developing the ability to visualize
these ‘agitations’ by modern brain imaging technology.
There seems to be little doubt that the normal ovarian
endocrine cycle provides the trigger in women with
CNS sensitivity to these endocrine changes. We are in
the process of explaining the reason for this sensitivity
incrementally – the more we learn, the more an explanation points towards specific neurotransmitters in the
CNS. A combination of molecular genetics, endocrinology, and brain imaging will certainly lead us to this
goal. In the meantime, we have a plethora of therapeutic
approaches to help us manage our patients until scientific
study leads to a cure.

INTRODUCTION
Despite several decades of research and progress in
knowledge on premenstrual syndrome (PMS), acceptance by most laypeople in Western countries and the
availability of reasonably effective treatment modalities, the definitions and diagnostic criteria for PMS
remain controversial. We are still far from a biomedical
and/or biopsychosocial model of a diagnostic entity
based on etiology, pathophysiology, phenomena, time
course, and treatment response. Even descriptive diagnoses are fragmented with at least two main pathways:
gynecological and psychiatric. Furthermore, there is
still a group that doubts the existence of PMS – mostly
on political–psychosocial grounds.
Diagnostic criteria are important for the clinical relevance and treatment of PMS as well as for delineation
of the public health impact. According to the criteria of
the American Psychiatric Association (APA) Diagnostic
and Statistical Manual, fourth edition (DSM-IV)1 and
DSM-IV – text revision (DSM-IV-TR)2 for premenstrual
dysphoric disorder (PMDD), the prevalence of that dysphoric premenstrual syndrome is widely cited as being
3–8% of women of reproductive age.3–10 However, if
the clinically relevant impairment, suffering, and distress
are considered as important, as opposed to the arbitrary
cut-off number of five symptoms, the 12 months prevalence of dysphoric PMS is closer to 20% of women
of reproductive age. The impact of definitions on the
reported prevalence is demonstrated in Table 2.1.
When viewed in relation to other mental disorders,16
it is demonstrated17 that PMS/PMDD should be viewed
as a major problem for the individual and the public.
According to the strict minimalist criteria, the impact
of PMDD on quality of life and social adjustment is
similar to that of dysthymic disorder and is comparable
to the impact of major depressive disorder (MDD) on

marital and parental social adjustment as well as housework and leisure functioning.17,18 Clinically relevant
amendments to the criteria would probably increase
the documented prevalence of dysphoric PMS and its
impact.
The public health impact of PMDD may be demonstrated by using the global burden of disease (GBD)
model and calculating the number of years of healthy
life lost to disability, or – in other words – the disability
adjusted life years (DALYs).19 Detailed conservative
considerations and calculations have been previously
published.17 The calculated burden of PMDD for the
USA as well as the European Union, using very strict
criteria for PMDD, is summarized in Table 2.2.
The actual total DALYs are probably much higher,
because the calculations in the table are limited to the
estimate of 5% of women who would meet strict criteria for PMDD and do not take into account women
with significant premenstrual impairment with only
3–4 symptoms, or who have only physical symptoms.
If global DALYs for PMS were to be calculated, the
number would be staggering.
Considering the clinical and public health impact of
premenstrual syndromes, an interdisciplinary internationally accepted diagnosis is needed.

EARLY DIAGNOSTIC CONCEPTS OF PMS21
As early as 190622 catamenial migraine was identified
as a menstrually related endocrinological disorder.
Various descriptions of premenstrual catamenial disorders
followed. In 1931, the American gynecologist Frank23
coined the term PMT – premenstrual tension, which
described mostly behavioral and mood symptoms and
their timeframe, 7–10 days before menstruation. It is of
interest that in the same year (1931) the prominent

psychoanalyst Karen Horney24 expressed a more
interdisciplinary approach, describing Prämenstruallen
Verstimmungen (premenstrual negative predispositions)
as a variety of syndromes – physical and mental – affecting
vulnerable women and triggered by changes in gonadal
hormones.
Although several hormonal and psychological treatment modalities of PMT were suggested, the definition
of PMT as a clinical entity was debated from time to
time with no operational solution. Notably the problems
were delineated by a distinguished interdisciplinary
panel gathered in New York in 1953,25 the same year
that the term premenstrual tension syndrome, PMTS
started to replace PMT. Later it was abbreviated to
PMS. Still, the diagnosis of PMS (or PMTS or PMT)

was a practical individual art depending on the physician’s specialty, awareness, philosophy, and skills. No
specific criteria were suggested, established, or accepted.
This has not been changed even with the more official
but vague inclusion of premenstrual tension syndrome
(PMTS) in the ICD nomenclature.

CURRENT DIAGNOSTIC ENTITIES OF PMS
ICD-10
The World Health Organization (WHO)’s International
Classification of Diseases, 10th edition (ICD-10),26
includes premenstrual tension syndrome (PMTS) in its

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DIAGNOSIS OF PMS/PMDD 11

Table 2.2 The burden of PMDD/PMS in the USA and the EU according to most conservative-strict definition:
disability adjusted life years (DALY)a lost
●
●
●
●
●
●
●
●

Severity weight of severe PMS
Age of onset of PMS
Prevalence in teenagers
Duration of disease 14–51 years
Cycles affected 481–22 (2 pregnancies and postpartum)
Average days of severe PMS per cycle
Total days/years of disorders
DALY (7.671 ⫻ 0.5)

Women ages 14–51 (USA); 15–49 (EU) 2000 census
75,580,000
⬎5%)
⬎3,779,000
Women who would meet criteria for PMDD (⬎
⬎14,492,465
Total DALYs, lost years of healthy life
The number would be even higher if all women suffering from PMS with impairment are counted

●

EU
91,445,000
⬎4,572,250
⬎17,534,579

Data from aMurray and Lopez,19 bWittchen et al,15 and cHylan et al.20

section of gynecological disorders, as a disorder of the
female genital organs. The significance of the ICD-10
diagnosis is that it focuses on the two main aspects of
PMS:
●
●

the association with the menstrual cycle
cyclicity and timing.

It requires that symptoms occur exclusively during
the premenstrual period and remit following menses.
It de-emphasizes the nature of specific symptoms or
phenomena. It only gives examples such as tension or
migraine or any other molimen – any menstrually related
symptoms. It does not specify any level of required
severity or impairment, no degree of change from the
non-symptomatic phase of the menstrual cycle, and no
differential diagnosis or exclusion criteria (Table 2.3).
The ICD-9 code for PMS is 625.4.

ACOG diagnostic criteria
Conceptually similar, but a step forward from the ICD10 criteria are the American College of Obstetricians
and Gynecologists (ACOG) diagnostic criteria for premenstrual syndrome (PMS)27 (Table 2.3).
The ACOG diagnostic criteria require the reporting
of at least any one of six affective or one of four somatic
symptoms that should exist during the 5 days before the
menses at each of three prior menstrual cycles and be

relieved within 4 days of onset of menses. They should
not exist until the periovulatory phase of the menstrual
cycle, be present in the absence of any pharmacological
therapy, be associated with impairment or dysfunction
in social or economic performance, and be prospectively
confirmed during two menstrual cycles.
The significance of the ACOG criteria is that they
acknowledge the importance of dysfunction and impairment, specify the symptomatic and the asymptomatic
periods, and require prospective confirmation of retrospective reports. In my opinion, the emphasis on timing,
with vagueness of nature of symptoms and requirement
for at least one symptom without a threshold of minimal
number of symptoms, is a conceptual and practical
strength of the ACOG criteria.

APA DSM-IV criteria
The most elaborate diagnostic criteria of a subtype of
PMS are the APA DSM-IV criteria for premenstrual dysphoric disorder – PMDD.1,2 This set of criteria requires
an initial retrospective report that symptoms, their
luteal–follicular cyclicity, luteal occurrences, and follicular absence have been presented for the majority of
cycles during the previous year. At least five out of 11
listed symptoms must be present; at least one of them
should be a major mood symptom – depression, anxiety,
irritability, or affective lability. Symptoms should cause
impairment and interfere with work, social activities,

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12 THE PREMENSTRUAL SYNDROMES

Table 2.3 Current diagnostic criteria for PMS/PMDD

Diagnostic entity (and
ICD-9 code)
Category
Temporal pattern

ICD-10

ACOG

DSM-IV

PMTS (625.4)

PMS (625.4)

PMDD (311)

Gynecology
Occur premenstrually
Remit following menses

Gynecology

Psychiatry

Occur 5 days before menses
Remit within 4 days of onset of
menses
No recurrence at least until
day 13 of cycle

Occur during the last week
before menses
Remit within few days after
onset of follicular phase
At least five symptoms, with at
least one of: depression,
anxiety, or tension, anger or
irritability, and monthly swings
Other qualifying symptoms are:
decreased interest, difficulty
concentrating, lack of energy,
changed sleep, overwhelmed,
out of control, change in
appetite
Other physical symptoms such
as breast tenderness, bloating
headaches, pain
Markedly interferes with work,
social activities, relationships
Most menstrual cycles during
past year
At least two consecutive cycles
Not merely an exacerbation of
another disorder
Not associated with
pharmacological, hormone,
alcohol or drug use or abuse

and/or relationships, not be an exacerbation of another
chronic disorder and be prospectively confirmed by daily
ratings during at least two consecutive cycles. Because of
differing opinions during the APA’s DSM-IV process,
PMDD is listed in the DSM-IV and DSM-IV-TR as one
of the criteria sets and axes provided for further study,
and is designated as ‘Depressive Disorder not otherwise
specified’ – ICD-9 code 311.
The three main diagnostic criteria are summarized in
Table 2.3.

UNSOLVED ISSUES WITH CURRENT
DIAGNOSTIC CRITERIA
The main shortcomings of the current diagnostic criteria are lack of universal agreement on the nature of the
PMS as well as lack of universal acceptance of the criteria
per se. The closest to universal acceptance is the ICD-10
entity. However, the PMTS description is vague and does
not provide specific diagnostic process and criteria:
actually, it just acknowledges the existence of the entity.

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DIAGNOSIS OF PMS/PMDD 13

Universal acceptance of a diagnostic entity is needed
for unified coding and for regulatory purposes. It
has financial ramifications for service delivery and
reimbursement as well as for prescriptions and their
reimbursements.
The lack of clear, acceptable definitions inhibits the
development of drugs and other treatments. Regulatory
agencies, like the US Food and Drug Administration
(FDA) and the European Union’s European Medicines
Agency (EMEA) require clear clinical indication for
pivotal clinical trials and clear projected outcome measures. In the USA, the indication of PMDD is acceptable
mainly because it is included in the influential DSM-IV
and follows its descriptive principles; PMS, though, is
still not acceptable despite the weight of the ACOG.
The implied dichotomy between the physical symptoms of PMS and the mental symptoms of PMDD is
arbitrary. The association between physical and mental
symptoms is still unclear, especially when any of them is
severe enough to cause dysfunction and/or distress. The
repeated and widely presumed reference to PMDD as a
severe form of PMS is not supported by data, either. It
also assumes a continuum of basically the same manifestation of an entity along a severity gradation and attributes lesser severity to perception of physical and other
non-dysphoric symptoms.
A major unsolved issue is the definition of PMDD as
a diagnostic entity, independent of PMS. This may well be
correct but so far data to the contrary are no less convincing. Most catamenial disorders (Table 2.4) are characterized as an episode whose phenomena and etiology
are similar to generally occurring disorders, but the timing
of the episode is entrained to the menstrual cycle – mostly
due to hormonal fluctuations. Therefore, the menstrually related changes trigger the occurrence of the specific
episode but do not influence the basic etiology and pathophysiology or the vulnerability to the parent disorder.
Only a few physical symptoms of PMS or catamenial disorders (e.g. breast tenderness) may be attributed to the
influence of estrogen or progesterone per se.
Review of the literature (for example, Refs 28–33)
demonstrates that PMDD may be a catamenial disorder like any other catamenial disorder. The phenomena
are similar to other depressions and anxiety disorders
and there is a statistical association with them. In some
cases treatment interventions and responses are similar.
A vulnerability–trigger conceptualization33–35 of
etiology and pathophysiology of PMS/PMDD suggests
that some women are vulnerable to develop specific
phenotypes of dysphoric disorders. Vulnerability implies
a symptomatic threshold in response to hormonal or
situational triggers. In many people symptoms appear
even without a currently known trigger and the course
of illness depends on currently unknown mechanisms.

Table 2.4 Is PMDD conceptually similar to the
following catamenial episodes?
●
●
●
●

Therefore, the main difference between DSM-IV affective and anxiety disorders and subtypes of PMS/PMDD
would be the added vulnerability to menstrually related
triggers and probably also an intact or strong normalization process that prevents the episode from extending
for a long time beyond the expiration of the menstrually related transitory stimulus.
According to this conceptualization, the distinction
between PMDD (or PMS) and premenstrual exacerbation (PME) of other mental or physical disorders may
not be substantial, especially when the exacerbations
are limited to or occur mostly during the premenstrual
period. Biologically, PMS and PME may represent stages
on a continuum of vulnerability–(threshold)–stimulus
interactions.
Even if PMDD is viewed as a separate entity, it presents
a plethora of unsolved issues.
Despite the acceptance of the PMDD entity by the US
FDA and despite several FDA-approved medications
for that indication, the definitions of PMDD are far from
being perfect. The main weakness of that diagnostic
entity is the requirement of endorsing five of the 11
listed symptoms. The reason for the choice of a specific
numerical threshold is unclear and it is not necessarily
clinically relevant. A significant proportion of women
report severe impairment but of only three or four
symptoms.15 They seek and certainly warrant treatment
no less than the 5% of women who report the highly
specific and restrictive five symptoms. Even though a
multitude of premenstrual dysphoric symptoms29 have

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14 THE PREMENSTRUAL SYNDROMES

been reported, only 11 are listed. There is no latitude for
accounting for other symptoms, even though for a
specific individual they may be no less severe than the
listed ones. The requirement of impairment of functioning does not consider the possibility of women who
manage to continue reasonable day-to-day functioning
despite having severe symptoms, but they do have severe
distress.
As is the case with most DSM-IV clinical entities, the
putatively quantitative measures are actually descriptive and are vaguely defined (e.g. ‘most menstrual cycles’,
‘most of the time’, ‘within few days’, ‘markedly’ interfere,
‘marked’ anxiety) and therefore are subject to additional subjective interpretations.
The contribution of inclusion of PMDD in the
DSM-IV to recognition of the entity and to improving
treatment of women suffering from PMS should not be
underestimated. The media coverage of that disorder as
well as industry promotion of FDA-approved medications certainly increased alertness of patients and clinicians as well as acceptance of the concept, but this does
not negate the need to further improve and refine the
diagnostic entity.
The ACOG criteria of PMS consider the individual
diversity of symptoms and avoid the trap of a specific
numerical symptom’s threshold. They follow previous
suggestions33 (and Mortola, unpublished work) for the
logic of PMS diagnosis but do not carry it to specificity
and well-rounded inclusiveness.

THE DURATION OF THE PREMENSTRUAL
PERIOD
The DSM-IV criteria require qualified symptoms to occur
during the week before menses, and the ACOG criteria
require them to occur within 5 days before menses. Both
do not specify for how many days should the symptoms
exist, nor does the DSM-IV specify how soon should
symptoms remit (‘within few days after the onset of
follicular phase’).
For clinical trials, inclusion criteria usually specify
‘severe symptoms for at least 4 days’ or ‘average severity
during 7 days’. When duration of premenstrual symptoms is reported20 it is apparent that there is a large
individual variability in the number of premenstrual
symptomatic days. The mean has been reported to be
6.1 days. However, in the USA, UK, and France, 44%,
36%, and 19% of women, respectively, reported in
retrospective telephone interviews that their PMS lasts
no longer than 3 days. Up to 10% of women with PMS
report duration of symptoms for the entire luteal phase
and 1–2% report that their symptoms actually included

the periovulatory period; 12–18% report only 1–2 symptomatic days. My clinical experience is that some women
may have extremely severe PMS symptoms for only 1–2
days, especially those with premenstrual manic or psychotic episodes.36 The possibility that different lengths of
the premenstrual phase of symptoms may be associated
with different phenotypes and underlying mechanisms has
not been fully elucidated yet, partially because women
with a very short premenstrual period (PMP) do not meet
criteria for current clinical trials, as is often the case for
women with a very long symptomatic phase.
The time-related different patterns of PMP and
their differentiation from chronic non-PMS pattern is
demonstrated in Figure 2.1.

PROPOSED DEFINITION AND DIAGNOSTIC
CRITERIA FOR PMS
If the diagnosis of PMS/PMDD is to be widely accepted,
two complementary conceptual procedural operational
steps should be taken. First, an international authoritative organization should take the lead in formulating
and establishing the diagnosis and its criteria. Indeed
the WHO should perform that task and update the ICD10 definition and criteria of PMTS, as a component of the
future ICD-11. The groundwork for such an update
has recently been performed. An interdisciplinary panel
of 16 experts from 13 countries in four continents recommended diagnostic criteria for PMS and their quantification for research.37 The panel was convened by
the World Psychiatric Association (WPA) Section on
Interdisciplinary Collaboration, and its recommendations
still need to be endorsed by diversified major professional
organizations of the related disciplines. Secondly, it should
be recognized that PMS is an interdisciplinary domain: it
involves many aspects of endocrinology, gynecology,
mental health, and clinical neurosciences, and several subdisciplines of internal medicine, as well as social and
developmental sciences. It is the domain of all of these
disciplines and none of them can claim it exclusively.
The main aspects of a proposed widely accepted definition of PMS have already been widely accepted:
●

●

The entity is distinguished from other similar entities mostly by its timing: symptoms appear mostly
cyclically during the luteal phase of the menstrual
cycle and disappear shortly following the beginning
of menses, and are temporally entrained to the menstrual cycle.
To be considered a disorder, symptoms should cause
impairment and/or dysfunction. I suggest to add
‘and/or distress’.

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DIAGNOSIS OF PMS/PMDD 15

a. PMS, classic

Extremely severe 5
Severe 4

b. PMS, symptoms
last most of the cycle
except mid-follicular phase

3
2
1
None 0

c. Perimenstrual
syndromes
d. Chronic disorder

Severity

5
4
3
2
1
0
5
4
3
2
1
0
5
4
3
2
1
0
5
4
3
2
1
0

M

O

M

O

M

M

O

M

O

M

M

O

M

O

M

M

O

M

O

M

M

O

M

O

M

e. No symptoms

Figure 2.1 PMS and non-PMS fluctuations of symptoms.

It is also quite widely accepted that individual vulnerability is an important contributor to the development of
PMS. It should be recognized that, as is increasingly suggested for affective disorders in general, there are probably diversified vulnerability traits to PMS.31 The
diversified vulnerabilities are probably associated with
diversified genotypes,36 pathophysiological processes
(e.g. 5-hydroxytryptamine (5-HT), ␥-aminobutyric acid
(GABA)35), and ensuing phenotypes. Once the concept
of multiple phenotypes or subtypes of PMS is accepted,

this is important not only for the diagnosis of PMS but
also for phenotype-targeted treatment, which is the ultimate purpose of appropriate diagnosis.
The main arguments in support of diversified vulnerabilities to PMS are:
●

Over 200 symptoms have been reported as appearing premenstrually; they involve many body systems
and none of them is exclusively related to the menstrual cycle per se.29,36–38

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16 THE PREMENSTRUAL SYNDROMES
●

●

●

The nature and clusters of symptoms are quite consistent from cycle to cycle within individual women,
although the severity may fluctuate.39
Individual women may tend to present with similar
symptoms at other times of physical, psychosocial,
or hormonal stress.
The rate of treatment response to any currently
approved medication for PMDD (currently only
selective serotonin reuptake inhibitors (SSRIs)) is
barely 20% better than placebo.40 One may suggest
that only a subgroup of women with PMS respond to
these medications. Subgroups with other vulnerabilities may respond to treatment modalities.41

The suggested diversified genotypes and phenotypes
lead to a need to de-emphasize the descriptive approach
to PMS and to replace it with a generalized approach that
has already been partly adopted by ACOG. Accordingly,
the following diagnostic criteria for PMS have been
proposed,33,42 but they are not widely accepted:
●

●

●

●

Any mood, behavioral or physical symptom(s), or
cluster(s) of symptoms that occur recurrently and cyclically during the luteal phase of the menstrual cycle.
The symptom(s) remit(s) shortly following the
beginning of menses and consistently do not exist
for at least 1 week of the follicular phase of most
menstrual cycles.
The symptom(s) cause emotional or physical distress and/or suffering and/or impairment in daily
functioning, and/or impairment in relationships.
The recurrence, cyclicity, and timing of the cycle,
and severity of the symptoms as well as existence of
a menstrually related symptom-free period are documented by daily monitoring and/or reports.

Whether or not exclusively premenstrually repeated
episodes of any disorder may be considered as PMS or a
catamenial disorder is a matter of definition. This may be
addressed as part of the differential diagnosis of PMS
(see Table 2.5).
Indeed, as is the case with many mental or physical
entities, there is a debate between ‘splitters’ (those who
are searching for specific phenotypes or subgroups of
patients with very specific and narrow clinical and etiological common denominators and similarities) and
‘lumpers’ (those who prefer a broader clinical approach
and are convinced that the differences between the
various subgroups and phenotypes are overpowered
by the similarities within the larger group). Although
I believe that there are multiple premenstrual syndromes with different vulnerabilities and phenotypes
but a common trigger, this debate has not been
resolved yet.

Similarly, there is no consensus on the role of catamenial episodes (see Table 2.4) as menstrually related
disorders (MRDs) and their relation with PMS. If the
definition of PMS is based mostly on timing and not on
descriptive phenomena, and if genotypes and dynamically evolving vulnerability35,42,43 contribute to specific
phenotypes of PMS, then one may argue that catamenial
episodes appearing during the premenstrual period are
subtypes of PMS (as long as they do not appear during
other times during the cycle). If the catamenial episodes
consistently appear at other times (non-premenstrual
phase of the menstrual cycle, e.g. periovulatory), then
they are a part of the broader definition of MRD.
As is the case with subtypes or phenotypes of PMS,
this is not just a heuristic discussion. It has direct clinical treatment implications. In the case of catamenial
episodes, treatment should involve the disorder-specific
intervention as well as suppression of hormonal cyclicity. This may also be the case with specific phenotypes
of PMS.
The diagnostic concept of multiple premenstrual syndromes, as opposed to a single PMS, was not accepted
by about half of the members of the international interdisciplinary consensus panel44 (consensus was considered when at least 14/16 participants agreed).
The panel agreed that a PMS ICD diagnostic code
should be incorporated in a new ‘Interdisciplinary diagnoses’ section and the title should be PMS – Premenstrual
Syndrome (different patterns of symptoms or clusters
of symptoms may appear as part of the syndrome).
The panel achieved a consensus on the pivotal role of
timing as a crucial criterion of PMS and settled on
‘2 weeks before menses in most menstrual cycles’, as
well as ‘remit following onset of menses’. Prospective
documentation of cyclicity is required, by clinician
and/or daily monitoring by the patient.
The panel required that the symptoms are not just an
exacerbation or worsening of another mental or physical chronic disorder, and recommended issues for field
trials that are quite similar to the ones that will be
described later. These field trails require quantification
of the diagnostic criteria that were also recommended
by the panel.

RESEARCH DIAGNOSTIC CRITERIA
FOR PMS/PMDD
Owing to the vagueness on severity and other definitions of the DSM-IV PMDD, quantitative replicable
definitions and procedures for diagnosis and outcome
measures had to be developed – to be translated into
inclusion and exclusion criteria for enrollment of patients
in clinical trials.

The research procedures are for quantification of
PMDD criteria of severity (quantify ‘marked’), duration
of symptomatic period, duration of non-symptomatic
period, and degree of impairment, as well as nonexistence of other diagnostic entities.
In addition, degree of change from non-symptomatic
to symptomatic periods and cyclicity are sometimes
measured.
The most acceptable research method to establish the
severity of symptoms, their entrainment to the menstrual cycle, and their fluctuation and cyclicity is by
daily rating forms (DRFs).
Most widely applied DRFs provide a range of severity
for each item, from non-existent to extremely severe.
There are some anchor definitions for each level of
severity. For research purposes, a cut-off point is introduced, mostly between mild and moderately severe.
However, that distinction is subjective and varies from
individual to individual. If there was an objective measure
of severity (at present, there is none) it would be subjectively described by some women as not severe and by
some others as very severe – according to their tolerance,
coping style, ability, personality, perception, and subjective definition of ‘what is severe’.
The difference between ‘mild’ and ‘moderate’ may
determine a woman’s eligibility or ineligibility for enrollment in a clinical trial, especially if it is a symptom that
would make the fifth required symptom of PMDD or is
a crucial perception of impairment.
Since the symptoms should be absent in the week post
menses, the same cut-off (though as an upper ceiling)
applies to the mid-follicular period as well. Here another

issue is pertinent. Since women are humans, there may
be external stressful situations during the mid-follicular
phase, and therefore women subjects may rate some of
the symptoms higher than ‘mild’ and thus would be
disqualified if clinical judgment was not exercised. An
average severity across 5 days may control for incidental stressful days, but even then a more flexible-realistic
schedule (e.g. allowing for several external stress-related
items above ‘mild’ severity) may reflect a representative
patient group.
Since the duration of PMS varies among patients, a
reasonable required duration of the severe symptoms
may be at least 2 days, with lesser severity during the
rest of the PMP.
Some DRFs provide an overall daily score for the
questionnaire, which may be averaged for the entire
designated PMP (usually 7 days) as well as for the midfollicular phase – allowing for calculation of total change
from mid-follicular to late-luteal phase, and hence a
measure of overall fluctuation and cyclicity. At least two
issues may be considered in this regard. First, a total
score does not reflect severity of PMS in a woman who
complains of only a few but very severe premenstrual
symptoms. This would also be the case with the determination of percentage change from mid-follicular to
late-luteal periods. Secondly, the percentage change
assumes a linear continuous score from non-existent to
extremely severe that is identical for all individuals.
This is not necessarily the case with the highly subjective
description at focus here. Furthermore, a combined
requirement of a minimal late-luteal total score and a
minimal percentage increase from mid-follicular to

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18 THE PREMENSTRUAL SYNDROMES

late-luteal phase may be too strict for some women and
very permissive for others (who may have many mild
symptoms which do not exist at mid-follicular phase).
The same considerations apply also to the impairment
items. However, there are women who do not have actual
premenstrual impairment of their performance but maintain their function with a high level of distress. This
should be considered as a measure of severity no lesser
than impairment in function.
For research purposes, regular menstrual cycles are
obligatory: usually 21–35 days are considered to be
‘regular’. However, currently there is no requirement for
the limit of individual cycle-to-cycle duration stability
within this wide range.

FUTURE DIRECTIONS FOR RESEARCH
ON THE DIAGNOSIS OF PMS/PMDD
The main diagnostic issues that, to my opinion, are still
unsolved are:
1.

2.

3.

4.

Are there multiple diversified premenstrual syndromes that also include diversified premenstrual
dysphoric phenotypes? This issue is also of crucial
importance for the understanding of the pathophysiology of PMS and effective treatment (beyond
the current efficacy ceiling of 60%).
If there are diversified phenotypes, can we move
beyond the DSM-IV-style descriptive arbitrary
cut-off points towards a diagnosis based on the
pattern(s) of symptoms, past history and time course,
biological changes (etiology and pathobiology),
and treatment outcome? Once phenotypes are established, are they specifically associated with specific
genotypes?
If our present understanding of PMS involves the
concept of vulnerability and menstrually related
trigger(s) of symptoms, then is it justified to distinguish between premenstrual syndromes and PMEs
or catamenial disorders? The difference may be the
degree of the threshold and the magnitude of the
trigger needed to cause expression of symptoms, but
not necessarily a fundamental difference between
premenstrual syndromes and PMEs. If the vulnerability level changes over time, and may increase or
decrease according to life events and their perception, as well as repeated assaults (kindling and
dynamically evolving vulnerability), then there may
be a continuum between at least some premenstrual syndromes, PMEs, and more chronic major
disorders – this notion deserves investigation.
What is a clinically relevant PMS (or PMDD)? When
do women warrant and benefit from treatment?

5.

Can we develop clinically relevant diagnostic procedures that would not require prospective monitoring of symptoms for two consecutive menstrual
cycles (which are too much of a burden for many
women and their primary care physicians)?

There are many more unsolved diagnostic issues of
PMS/PMDD, even before we tackle issues of underlying
mechanisms that may vary from phenotype to phenotype.

SHOULD PMS BE REGARDED AN
ENDOCRINE CONDITION OR AS
A BRAIN DISORDER?
Triggered by sex steroids produced by the ovaries, premenstrual syndrome (PMS) and premenstrual dysphoric
disorder (PMDD) may be, and have often been, regarded
primarily as endocrine conditions. Attempts to explain,
in terms of differences with respect to hormone levels,
why certain women are afflicted by premenstrual symptoms, while other women are spared from such complaints, however, have consistently failed. Therefore, it is
nowadays generally agreed that women with premenstrual complaints differ from controls not with respect
to ovarian function, but with respect to how responsive
the target organs are to the influence of gonadal steroids.
Supporting this view, administration of exogenous sexual
hormones following the suppression of the endogenous
gonadal steroid production elicits PMS-like complaints
in women with PMS but not in controls.1
One important target organ for sex steroids is the
central nervous system. Receptors for sex hormones are
thus abundant in many brain regions including the
amygdala and the hypothalamus. Since mood and behavioral symptoms are key features of PMS, the brain obviously is where underlying processes at least partly must
be sought. Consequently, a better understanding of the
mechanisms underlying PMS clearly requires insight
into the neurochemical basis of the influence of sex
steroids in relation to mood and behavior and why
certain individuals are particularly sensitive to this
influence. Hence, studies of PMS have to deal with the
same difficulties, and apply the same methodological
approaches, as research on the pathophysiology of other
psychiatric disorders.
Two factors render studies on the mechanisms
underlying psychiatric illness more difficult than other

fields of medical research. First, the brain is much more
complex than any other organ; hence, our knowledge
of how it operates to produce consciousness, thoughts,
memories, executive functioning, and emotions is as yet
very limited. And secondly, it is – as compared to many
other organs – relatively inaccessible for exploration.
Because of these difficulties, it is as yet impossible
to measure to what extent a certain individual is
characterized – for example – by shortage or excess of
a certain brain transmitter.
Notwithstanding these problems, over the past
50 years, very reasonable hypotheses concerning the
involvement of specific brain transmitters in conditions
such as depression, anxiety, schizophrenia, and attention
deficit hyperactivity disorder have been formulated.
These hypotheses have, without exception, been based
primarily on pharmacological observations: whereas
certain drugs have been found, accidentally, to reduce
the symptoms of the condition in question, other compounds have been found to aggravate them. And by
then analyzing how these different compounds influence brain neurotransmitters, using animal experiments, researchers have been able to draw tentative
conclusions regarding the pathophysiology underlying
the studied condition.2 Subsequently, usually decades
later, it has often been possible to obtain at least partial
confirmation of these theories by means of other
methodological approaches, such as brain imaging3,4
or genotyping.5 But the foundation of theories linking
brain neurotransmitters to psychiatric disorders has
always been the presumed mechanism of action of
drugs.
With respect to the brain mechanisms underlying PMS,
one particular neurotransmitter, serotonin, has been
proposed to play a key role. As is the case for other theories implicating specific transmitters in specific conditions, also this hypothesis is first and foremost based on

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22 THE PREMENSTRUAL SYNDROMES

pharmacological data: whereas drugs facilitating brain
serotonergic transmission effectively reduce the symptoms
of PMS, treatments counteracting serotonergic activity
may aggravate them. In addition to these findings, there
are however also reports, though difficult to interpret,
suggesting that women with PMS differ from controls
with respect to serotonergic activity. In this chapter, the
different arguments supporting an involvement of serotonin in PMS will be presented and discussed.

HOW IS HUMAN BEHAVIOR INFLUENCED
BY SEROTONIN?
Serotonin is a monoamine, formed from the essential
amino acid tryptophan, with 5-hydroxytryptophan as
intermediate.6 Whereas the cell bodies of the neurons
using serotonin as transmitter are all localized to the
brainstem, serotonergic nerve terminals are found in
most parts of the brain. The effects of this transmitter
on adjacent neurons are mediated by at least 15 receptor subtypes, the different functions of which are as yet
poorly understood.
Serotonin has long since been assumed to be of importance for the regulation of mood and behavior, partly
because of observations made in preclinical studies,
and partly because of the antidepressant and anxietyreducing effect exerted by serotonin-facilitating drugs,
such as the serotonin reuptake inhibitors (SRIs) (see
below). Recently, the importance of serotonin for depression and anxiety has been reinforced by studies applying
brain imaging4 and/or molecular genetics.5,7,8
Although serotonin has been implicated in psychiatric
conditions as disparate as depression, obsessive compulsive disorder, and panic disorder, little is known regarding
the normal, physiological role of this transmitter. Interestingly, however, the most clear-cut changes in the
behavior of rodents exposed to serotonin depletion is
an increase in aggression and sexual activity,6 i.e. those
aspects of behavior that are most clearly sex steroiddriven. These findings may suggest that a major physiological task for serotonin in rats and mice is to modulate
or dampen sex steroid-driven behavior. That this may
be the case not only in rodents but also in humans gains
support from the fact that reduced libido is probably
the most common side effect of long-term treatment
with SRIs.9
Studies showing sex steroids to influence serotonin
transmission in rodents10–14 and non-human primates15,16
suggest that the effects of gonadal hormones on behavior may be mediated in part by an influence on serotonergic pathways. However, an alternative scenario
would be that sex steroids influence neuronal circuits
regulating mood and behavior, which do not constitute

serotonergic neurons per se, but are under the dampening influence of serotonergic terminals. Reinforcing the
notion that interactions between sex steroids and serotonin may be of clinical importance, almost all indications for SRIs – including depression, dysthymia, social
phobia, panic disorder, generalized anxiety disorder, and
eating disorders – display a marked gender difference in
prevalence, being considerably more common in women
than in men.
If it is true that a major role for serotonin is to dampen
the influence of sex steroids on behavior, the theory that
serotonin is of importance for PMS, one of the most
obvious examples of sex steroids influencing behavior,
is not farfetched, and even less so given the fact that
enhanced irritability is a cardinal symptom of PMS, and,
at the same time, one of the most characteristic features
of serotonin-depleted animals. Given what we know
from animal studies regarding the neurochemical
regulation of aggression, for any condition in which
irritability and anger are prominent symptoms, an
involvement of serotonin should in fact be suspected.

SEROTONIN REUPTAKE INHIBITORS
IN PMS
The most well-established way of facilitating brain serotonergic neurotransmission is to block the serotonin
transporter, i.e. the protein inactivating serotonin by
transporting this molecule from the synaptic cleft back
into the presynaptic neuron. Such an effect may be
achieved by SRIs, some of which selectively inhibit the
reuptake of serotonin only (selective SRIs ⫽ SSRIs), and
some of which inhibit the reuptake of both serotonin
and norepinephrine (tricyclic antidepressants and serotonin/norepinephrine reuptake inhibitors ⫽ SNRIs).
To a large extent, the notion that serotonergic neurons
are part of – or capable of influencing – the neuronal
networks that generate premenstrual changes in mood
and behavior stems from the observation that SRIs very
effectively reduce such symptoms. This has now been
shown with the tricyclic antidepressant clomipramine,
the selective SRIs citalopram, escitalopram, fluoxetine,
paroxetine, and sertraline, and the SNRI venlafaxine.17–19
In addition to reducing the symptoms of PMS, the SRIs
are also antidepressants. Whereas studies aiming to reveal
an effect of these treatments in depression however
sometimes fail to show a difference between active drug
and placebo, due to insufficient statistical power, the
superiority of SRIs over placebo in PMS/PMDD has
been robustly replicated in a large number of consecutive
studies, one small early trial being the sole exception.17–19
In PMS patients with irritability or depressed mood as
the most prominent symptoms, the response rate to an

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PREMENSTRUAL SYNDROME: A CASE OF SEROTONERGIC DYSFUNCTION? 23

SRI may be around 90%, and the effect size – which is
a measure of the difference between active drug and
placebo – for the most responsive symptoms, such as
irritability, as high as 1.4, which is much higher than
what is usually found in studies on the effect of SRIs in
other conditions.20 It may hence be argued that premenstrual irritability is an extraordinarily SRI-responsive
condition, more so than, e.g. depression.
For the treatment of depression, reuptake inhibitors
selectively or primarily influencing serotonin appear to
be neither more nor less effective than reuptake inhibitors
primarily influencing norepinephrine. For the treatment
of PMS, on the other hand, only reuptake inhibitors
with a marked effect on serotonin, such as those listed
above, seem to be effective.21–23 These findings suggest
that the effect of SRIs in PMS is not equivalent to the
antidepressant effect of these drugs, and underline the
importance of serotonin, rather than norepinephrine,
for the influence of antidepressants in PMS.
Animal studies have revealed an immediate increase
in synaptic serotonin concentrations following SRI
administration,24 and there are also reasons to assume
that SRIs are capable of exerting an almost immediate
facilitation of serotonin activity in humans. Endocrine
responses to these drugs,25 as well as some of the side
effects (including nausea26) and influence on sexual
function27, hence appear shortly after drug intake. In
spite of this, the beneficial effect of SRIs in depression
and several anxiety disorders usually requires several
weeks of treatment. Interestingly, such a delay in onset
is not seen when these drugs are used for the treatment
of PMS; SRIs are thus capable of reducing premenstrual irritability within a few days after treatment has
started. As first shown for clomipramine28 and later
confirmed for citalopram, escitalopram, fluoxetine,
paroxetine, and sertraline,19 this short onset of action
renders intermittent administration of SRIs, during
luteal phases only, a feasible alternative to continuous
administration.
The difference between PMS and other indications
with respect to the onset of action of SRIs has prompted
some authors to suggest that the effect of these drugs in
PMS must be unrelated to serotonin. Such a conclusion
is however unjustified, since SRIs do exert a prompt
effect on serotonergic transmission; the speed of onset
of the clinical response hence does not at all argue
against the effect being mediated by serotonin. Yet the
difference between PMS on the one hand, and depression
and other indications on the other, with respect to the
onset of action of SRIs, reinforces the assumption that
the effect in PMS is not equivalent to the antidepressant
and antianxiety effects of these drugs, but probably
mediated by other serotonergic pathways. Of considerable interest in this context are studies suggesting that

symptoms such as anger and affect lability, i.e. two cardinal symptoms of PMS, respond within a very short onset
of action to SRIs also when being the consequence of
conditions such as dementia, stroke or brain injury.29–32
Moreover, SRIs have been shown to reduce estrous
cycle-related aggression without delay in a rodent
model of PMS.33

EFFECTS OF OTHER MEANS OF
MODULATING SEROTONERGIC
TRANSMISSION
If the assumption that SRIs reduce premenstrual symptoms by facilitating serotonergic transmission is correct,
then other treatments enhancing serotonin activity would
be expected to reduce premenstrual complaints. Conversely, manipulations reducing serotonergic activity
would be expected to aggravate or trigger symptoms
and/or to reverse the symptom-reducing effect of SRIs.
Indeed, a large number of observations indicate this to
be the case:
1.

2.

3.

4.

5.

6.

mCPP and fenfluramine – two compounds known
to release serotonin into the synaptic cleft by interacting with the transporter, but in a different way as
compared with the SRIs34 – have both been reported
to reduce premenstrual symptoms.35,36
The serotonin precursor tryptophan, which should
be expected to cause at least a moderate increase in
serotonin formation, has also been shown to be
superior to placebo for this condition.37
Pyridoxine, which is a cofactor for an enzyme of
critical importance for serotonin formation, also
appears to exert some (though modest) beneficial
effect.38
Buspirone, which is a partial agonist at the serotonergic 5HT1A receptor, has been shown to be
superior to placebo in reducing at least one important premenstrual symptom, i.e. irritability.39
Depletion of tryptophan from the diet, leading to a
reduction in serotonergic transmission, has been
shown to aggravate premenstrual irritability.40
The symptom-reducing effect of SRIs in PMS is at
least partly counteracted by administration of a
serotonin receptor antagonist, metergoline.41

Taken together, these observations speak very strongly
in favor of the hypothesis that premenstrual dysphoria
may indeed be dampened by serotonergic neurons.
Given this body of evidence, the notion sometimes put
forward that the effect of some of the SRIs in PMS is in
fact independent of serotonin, and instead mediated by
other mechanisms,42 seems somewhat unlikely.

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24 THE PREMENSTRUAL SYNDROMES

IS PMS DUE TO SEROTONERGIC
DYSFUNCTION?
Needless to say, the fact that enhancing or reducing serotonergic activity may alleviate or aggravate PMS does not
necessarily mean that the symptoms are the result of
serotonergic dysfunction. As discussed below, many
studies however do lend support to the notion that
women with PMS/PMDD differ from controls with
respect to various indices of serotonergic activity, indicating that serotonin in fact may play a significant part
in the pathophysiology of this condition.
One tentative way of assessing serotonergic activity in
living humans is to utilize the fact that certain serotoninrelated proteins, including the serotonin transporter and
the serotonin-metabolizing enzyme monoamine oxidase
(MAO), are expressed not only by serotonergic neurons
in the brain but also by platelets. Several studies
comparing PMS subjects and controls with respect to
serotonin uptake into thrombocytes, platelet serotonin
transporter density, and platelet MAO activity, do suggest
a difference either throughout the menstrual cycle or at
a certain phase of the cycle.43,44 Although it remains
unclear to what extent these peripheral markers reflect
brain serotonin activity, and how the observed differences should be interpreted in terms of function, these
findings provide some evidence for the notion that PMS
may be associated with aberrations in serotonergic
activity.
Hypothalamic serotonergic neurons exert a stimulatory influence on the release of prolactin from the pituitary. One tentative way of addressing the function of
brain serotonergic neurons and/or the responsiveness of
central postsynaptic serotonin receptors is to assess the
prolactin response to indirect or direct serotonin receptor
agonists. Several studies indicate that women with PMS
differ from controls also with respect to this parameter.45–47 However, how this measure corresponds to the
activity of those serotonergic neurons that are involved
in the regulation of mood and behavior remains to be
clarified.
Another crude way of assessing brain serotonergic
transmission is to measure levels of the serotonin
metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the
cerebrospinal fluid. One study has reported reduced
levels of the ratio between the dopamine metabolite
homovanillic acid and 5-HIAA in women with PMS.48
This finding is of some interest since a similar aberration
has previously been reported in subjects with depression,
but it cannot be easily interpreted in terms of function.
A more sophisticated strategy to assess brain serotonergic transmission in humans than those mentioned
above is the use of brain imaging techniques, such as
positron emission tomography. Although research on

PMS using this method are as yet sparse, there are two
recent pilot studies suggesting that symptomatic women
differ from non-symptomatic controls with respect to
uptake of a serotonin precursor and density of serotonergic 5HT1A receptors, respectively.49,50 Both these
studies are small, and should be interpreted with caution
until replicated, but they do lend further support to the
notion that PMS may be associated with abnormal
serotonin activity.
It should be emphasized that all of the different techniques mentioned above yield results that are difficult
to interpret, and that they provide, at best, an indirect
and/or very limited insight into the status of the different serotonergic pathways in the brain. Moreover, most
of the studies that have been published in this field are
small, and should for this reason be regarded as preliminary until replicated. Notwithstanding these caveats,
the fact that such a large number of studies indicate
that PMS women and controls differ significantly with
respect to various serotonin-related indices supports
the notion that PMS is indeed associated with serotonergic dysfunction. In this context, the possible influence
of publication bias, i.e. the tendency for studies finding
a difference to get published more often than studies
not finding a difference, should however not be ignored.
If certain variants of serotonin-related genes were found
to increase the susceptibility to PMS, this would provide a
reasonable explanation both to the symptoms characterizing this condition and to the many positive findings
regarding serotonin-related biological markers, including
peripheral indices of serotonergic function, that have been
published. However, association studies showing a relationship between serotonin-related genes and PMS have
yet to be published. In one study, women with PMS were
found to display reduced platelet density of the serotonin
transporter, but this difference could not be linked to any
of the more well-known polymorphisms in the serotonin
transporter gene.43
To conclude, the hypothesis that the enhanced responsiveness to sex steroids in women with PMS is at least
partly due to a dysfunction in brain serotonergic neurons
is not far-fetched and gains some support from the
available literature, but remains to be confirmed. Brain
imaging studies and extensive studies of serotonin-related
genes in large and well-characterized cohorts should
shed further light on this issue.

THE POSSIBLE ROLE OF SEROTONIN IN
THE PATHOPHYSIOLOGY OF SOMATIC
SYMPTOMS
One issue that has for long been debated, but remains
unresolved, is if premenstrual somatic symptoms–such

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PREMENSTRUAL SYNDROME: A CASE OF SEROTONERGIC DYSFUNCTION? 25

as breast tenderness, bloating, joint and muscle pain,
and headache–are due to the influence of sex steroids in
the brain, modulating the subject’s awareness of minor
bodily changes, or to direct effects of sex steroids in
hormone-responsive tissues in the periphery.
Supporting the former notion, several studies have
failed to confirm fluid retention or breast enlargement
by objective means in women reporting these symptoms.51
Moreover, many studies have demonstrated that SRIs
reduce not only mood and behavioral symptoms but also
somatic complaints. Worth considering in this context is
the fact that SRIs have been reported to influence the
sensitivity to pain also in other conditions.52
On the other hand, it should be emphasized that the
SRIs exert a more robust effect on premenstrual mood
and behavioral symptoms than on somatic symptoms,
a difference that is particularly evident when the treatment is given intermittently20. Moreover for one common
premenstrual symptom, headache, no superiority of
SRIs over placebo has been reported. Hence, the suggestion put forward in this chapter that serotonin is
critically involved in the pathophysiology of PMS is
probably more relevant for the mood and behavioral
aspects of this syndrome than for the somatic complaints.

UNRESOLVED ISSUES
To conclude, there is strong evidence to support the
notion that sex steroids and serotonergic neurons interact, and that an important task for the serotonergic
pathways is to dampen sex steroid-driven behavior, such
as aggression and sexual activity. In all likelihood, the
rapid and very impressive effect of SRIs on many of the
cardinal symptoms of PMS, such as irritability and affect
lability, should be regarded as a manifestation of this
interaction, and of the well-established inhibitory influence of serotonin on anger and irritability. Although there
are reasons to believe that the amygdala and the hypothalamus are brain areas of particular importance in
this context, much more work is required to map the
pathways involved, and to clarify how and where sex
steroids and serotonergic neurons interact. It is also
important to elucidate which of the many different
serotonin receptors that mediate these effects of serotonin,
and with which other transmitters serotonin interacts in
this context. In particular, the interplay between serotonin and another transmitter, dopamine, that is known
to exert effects opposite to those of serotonin on
aggression, warrants further study.
Although the efficacy of SRIs in PMS is well established, it remains to be clarified if women with premenstrual symptoms differ from controls with respect to
serotonin activity, or if the mechanisms making certain

women particularly responsive to the influence of sex
steroids reside elsewhere. Studies of serotonin-related
genes, assessment of brain serotonergic activity using
brain imaging techniques, and projects combining
these strategies are likely to shed further light on this
issue.

INTRODUCTION
Gynecological practice is almost always informed by an
objective test or visual information on which to base
diagnosis and provide treatment. No such objective
tests are available for quantification for premenstrual
syndrome/premenstrual dysphoric disorder (PMS/PMDD),
and this may be a challenge for gynecologists treating
patients or undertaking research.
Psychiatrists are used to this problem in the diagnosis, management, and documentation of most psychiatric disorders and, while they are well acquainted with
disorders that are periodic in nature, it is rare that
prospective assessment and the wait for repeated menstrual cycles impacts on their practice regularly. Similarly, they are less well acquainted with the vagaries of
the menstrual cycle, its endocrinology and its other
symptoms.
As we know, PMS and even PMDD are commonly
encountered amongst women of reproductive age, and
these can have a major impact. (see Chapter 6).
Literally hundreds of symptoms have been described,
spanning a spectrum of mood and physical disturbance,
and so it is not surprising that symptomatology overlaps with many other medical problems. We will see in
several of the following chapters that the exclusion of
both psychiatric and organic medical/gynecological disorders is of critical importance: gynecological disorders
that may be confused include pelvic pain syndrome,
endometriosis, dysmenorrhea, and the perimenopause.
Psychological disorders to be distinguished, amongst
many others, include subtypes of depression, personality disorder, anxiety disorders, and seasonal affective
disorder. Investigators lack agreement regarding the
particular symptoms that define PMS and the specific
methodology to diagnose this condition. Whether the

method of assessment needs to be different for clinical
purposes and research is also a matter for debate.
There is currently no objective means of assessing
PMS, and clinical diagnosis relies predominantly on the
subjective self-reporting of symptomatology. If we look
again at the criteria required for the diagnosis of PMS
and PMDD, it is clear that several factors must be
quantified.
Any technique needs to provide an easily completed
means of assessing individual symptoms on a prospective daily basis. To ensure compliance, this must be
simple and not time consuming for the patient. The
symptoms should be easily converted into numerical
data and so free text should be avoided. The first aim is
to demonstrate that symptoms occur in the luteal phase
and, perhaps most importantly, to show that they
resolve by the end of menstruation. Secondly, the severity of symptoms needs to be quantified in a numerical
format. Thirdly, a means of assessing whether or not
there is an underlying psychiatric disorder and how this
is to be quantified needs consideration; psychiatric
interview, rating scales, or questionnaires for psychological illness are all possibilities. At its most simple,
given that there is considerable overlap between symptoms of PMS/PMDD and those of other psychological
disorders, the absence of symptoms in the follicular
phase on PMS/PMDD scales may well suffice for clinical practice for the exclusion of depression but probably
not for disorders such as obsessive compulsive disorder
(OCD) and post-traumatic stress disorder (PTSD)
which require structured psychiatric interview. Finally,
an important factor which we must measure, and in fact
the key factor which enables us to distinguish between
physiological premenstrual symptoms, PMS, and PMDD,
is the determination of the impact on normal functioning,
well-being, and interpersonal relationships.

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28 THE PREMENSTRUAL SYNDROMES

METHODS OF MEASUREMENT
REPORTED TO DATE
Early research projects attempted to use rating scales
that were essentially established and designed to quantify other psychiatric and psychological conditions.
Examples of this are the use of the Hamilton Rating
Scale for Depression1 and the Beck Depression
Inventory.2 The lack of specificity of these techniques
to quantify PMS led to the development of new
‘bespoke’ techniques.
The earliest published measure specific to premenstrual symptoms was the Moos’ Menstrual Distress
Questionnaire (MDQ),3 which used a 47-item 0–6 rating
scale. The first use of visual analog scales (VAS) was published as the Premenstrual Mood Index, which was used
for the first time within the context of a randomized clinical trial of spironolactone at the University of
Nottingham, UK.4 We will look at the use of VAS first.

Visual analog scales
VAS techniques demonstrate admirably the character
and cyclicity of symptoms. It is likely that visual analog
scales (VAS) are the most sensitive measure of PMS/
PMDD, as they allow a continuous rating. When first
used back in 1976, each score had to be measured by
hand, and this was tedious and onerous. The VAS can
be used to look at individual scores and their response
to therapy or a global score. Visual analog scales have
been found to be an effective tool in measuring the
change in premenstrual symptoms over time, and their
validity and reliability have since been well documented.4–6 Bipolar visual analog scales, which record
mood changes, differ in one important respect from the
more usual unipolar ratings; the 100 mm line has both
positive and negative mood adjectives, with the midline
being ‘a normal day’; they are thus rated either side of
50 mm scores. Bipolar visual analog scales are more
difficult to handle in a statistical sense.
Unipolar VAS consists again of a 100 mm horizontal
line with vertical line anchors at each end. The anchors
are 0 ⫽ ‘not at all’ (i.e. the way you normally feel when
you don’t have premenstrual symptoms) and 100 ⫽
‘extreme symptoms’ (i.e. the way you feel when your
premenstrual symptoms are at their worst). Data collected from more recent trials of women with severe
premenstrual symptoms indicate that the use of the
revised VAS, which better reflects the current DSM-IV
(Diagnosis and Statistical Manual of Mental Disorders,
fourth edition) definition of PMDD, provides a reliable
measure of premenstrual symptoms when evaluated
against the well-validated Premenstrual Tension

Syndrome – Observer (PMTS-O). It is more user
friendly and also improves compliance. However, the
relentless measuring of the 100 mm lines of the scales
was at the time a disincentive to further development of
the method.7 Later on, the ability to optically read the
scores and to provide a measuring technique on touchsensitive PDA screens showed the promise of greater
simplicity and utility (Figure 4.1). This is discussed in
detail later.

OTHER RATING SCALES
The original Moos MDQ had significant limitations,
mainly related to the specificity of the symptoms. Even
so, this is the model on which most other PMS rating
techniques were based. It used a 46-item 0–6 rating
scale; the various newer techniques rate from 0 to 3, 4,
5, 6, or 7, using categorical rating scales. The cynic
might observe that there are about the same number of
scales as there are research groups. Early scales
included the Clinical Global Impression Scale (CGIS),
the Global Assessment Scale (GAS),8 the Steiner SelfRating Scale,9 while later the more widely used scales
included Premenstrual Assessment Form (PAF),10
Prospective Record of the Impact and Severity of
Menstrual Symptoms (PRISM),11 and the Calendar of
Premenstrual Experiences (COPE).12 These and many
other tools used over the past 30 years are summarized
in Table 4.1.

The Daily Record of Severity of Problems
During the evolution of these various methods, the
DSM-III and DSM-IV criteria23 were developed for late
luteal phase dysphoric disorder (LLPDD), and then
PMDD. In line with that, in 1990, Endicott and
Harrison20 published the somewhat simple tool named
Daily Record of Severity of Problems (DRSP). DRSP
was developed to help individual women and their
therapist assess the nature, severity, and timing of onset
and offset of problems which may develop during specific phases of the menstrual cycle. The feelings and
behaviors which are to be rated each day are those
which make up the diagnostic criteria for PMDD.
Completion of such rating is essential to determine the
nature of the problem being experienced.20
Daily ratings made for several menstrual cycles help
to establish when specific symptoms first appear or
become more severe, how severe they become, how
much impairment in functioning they cause, and when
they go away or become less severe. The pattern of change
in the symptoms helps the woman and her therapist
to determine which of the following conditions are

Premenstrual worsening of her ongoing condition,
which is present throughout her cycle.
PMDD with patterns of changes that clearly meet
criteria.
PMS that is clearly present but does not meet the
severity or impairment criteria for PMDD.
Symptoms and impairment that show no evidence
of being linked to phases of the menstrual cycle.

The reason such a diagnostic evaluation is important is
that it will identify the diagnosis and guide the treatment
of the condition (Figure 4.2)

The Premenstrual Symptoms Screening Tool
The Premenstrual Symptoms Screening Tool (PSST) is a
simple user-friendly screening tool devised by Steiner
et al22 to identify women who suffer from severe
PMS/PMDD and who are likely to benefit from treatment. The PSST reflects and translates categorical
DSM-IV criteria into a rating scale with degrees of
severity and impact of premenstrual symptoms. It is
less time consuming and more practical than two cycles
of prospective charting and, hence, is an important
starting point for further assessment. Following screening, the clinician still must rule out other psychiatric

and medical conditions and, if in doubt, more comprehensive assessment measures including prospective
charting should be initiated (Figure 4.3).
This chart has the potential to provide a simple easyto-used chart for clinical purposes but probably not for
research. Even for clinical purposes, most clinicians
believe it still needs to be validated against the DRSP.
When using any chart for either research or clinical
purposes, ideally, symptoms should be rated prospectively in order to avoid the inaccuracies inherent in
retrospective rating, including the incorrect recall of
symptom timing and exaggeration of symptom severity.
Symptoms recorded over several cycles will illustrate
any inter-cycle variability in the nature and severity of
symptoms. Statistical measures have to be used to
establish if a cyclical change exists or not.
Quantifying severity with VAS and other techniques
poses problems. In 1983 the National Institute of
Mental Health workshop on PMS/PMDD stated that
premenstrual changes should show at least 30% increase from the intensity of symptoms measured in the follicular phase (i.e. on days 5–10 of the menstrual cycle),
compared with those measured in the premenstrual
phase (on the 6 days before menstruation). Many of
those involved in that workshop consider the 30%
change in the ratings of symptoms has been shown to
be too liberal and a poor discriminator when comparing women with self-reported severe PMS, women
using contraceptives whose natural cyclicity has been

100 mm line at either end of which are
opposing adjectives representing the
symptoms

Magos and
Studd 198819

Premenstrual Tension-Cator
(PMT-Cator)

Five symptoms rated 0–3S

aGuy

197616

(Continued)

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QUANTIFICATION OF PMS AND PMDD 31

Table 4.1 (Continued)
Reference

Method

Mortola et al 199012

Calendar of Premenstrual
Experiences (COPE)

Endicott and
Harrison 199020

Daily Record of Severity of
Problems (DRSP)

22-item rated 0–6 specifically for symptoms
of PMDD

aRivera-Tovar

Daily Assessment Form (DAF)

33-item symptom checklist rated from 0
(none) to 6 (extreme)

Premenstrual Screening Tool (PSST)

Retrospective 0–3 scale. Retrospective for PMDD

and

Comment

Frank 199021
Steiner et al 200322
aMethods

originally designed for diagnoses other than PMS or PMDD.

suppressed, and women with normal cyclicity who
report no premenstrual symptoms.24,25 They now believe
that if a 30% increase is to be used, it must relate to the
symptom score range rather than baseline. Additionally, Gallant et al emphasized that what may be
more clinically relevant is women’s perceptions of variations in social and occupational functioning and ‘the
way in which having PMS is meaningful in a woman’s
life’. The authors’ concern is that ever more stringent
criteria might result in the exclusion from studies or
treatment of significantly troubled individuals.
As early as 1986, Magos et al had applied Trigg’s
trend analysis18 to evaluating severity and cyclicity and
produced quite a useful tool for this purpose. Ekholm
et al26 compared four different methods to assess the
cyclicity and severity, based on the daily prospective
symptoms rating. The methods compared were:
●
●
●
●

the non-parametric Mann–Whitney U-test,
effect size
run-test
a 30% of change in symptom degree between the
follicular and the luteal phases.

They concluded that three of the methods used seemed
to correctly identify the same patients as having or not
having cyclical changes. However, some differences in
the outcome of validity testing and the 30% change
methods seemed less valid than the other three
methods.

DIAGNOSIS AND STATISTICAL MANUAL
OF MENTAL DISORDERS (DSM-IV)
The diagnosis of PMS was operationalized with the
introduction of the term ‘late luteal phase dysphoric

disorder’ (LLPDD) into DSM-III-R (American Psychiatric Association, 1987) under the section headed
‘Proposed diagnostic categories needing further study’.
Subsequently a work group on LLPDD reported to the
Diagnosis and Statistical Manual of Mental Disorders
(DSM) IV task force, culminating in its inclusion in
DSM-IV23 as ‘Premenstrual dysphoric disorder’ in the
section ‘Mood disorders not otherwise specified’, with
its clinical criteria laid out in Appendix B – ‘For further
study’ (Table 4.2). PMDD criteria require the presence
of both certain types or number of symptoms (five of
11 symptoms present premenstrually, at least one being
one of four mood symptoms – depression, anxiety, irritability, and affective lability) and certain phenomenal
characteristics (present premenstrually and absent postmenstrually). Symptoms should cause impairment and
interference with work/school/social activity and/or
relationships premenstrually, not be an exacerbation of
another chronic disorder, and be prospectively confirmed by daily ratings during at least two consecutive
cycles. A change in symptoms from the follicular to
the luteal phase of at least 50% is suggested for the
diagnosis of PMDD.
There is little question that the creation of diagnostic
criteria has improved the generalizability of findings in
psychiatric research by assuring greater cross-study
sample homogeneity. While this has certainly been true
for PMS, questions can be legitimately raised about the
stringency of the criteria and the means of their operationalization.
Unfortunately, the DSM-IV does not specify for how
many days the symptoms should exist, nor does it
specify how soon the symptoms should remit: additionally, it fails to pay much attention to the importance of
physical symptoms. For clinical trials, inclusion criteria
usually specify ‘severe symptoms for at least 4 days’ or

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32 THE PREMENSTRUAL SYNDROMES
DAILY RECORD OF SEVERITY OF PROBLEMS
Name or Initials----------------------------------------Month/Year--------------------------------------------Each evening note the degree to which you experienced each of the problems listed below. Put an “x” in the box which
corresponds to the severity: 1 - not at all, 2 - minimal, 3 - mild, 4 - moderate, 5 - severe, 6 - extreme.
BLEEDING
Cycle Day

1

2

Felt depressed, sad, “down”, or “blue”
Felt hopeless
Felt worthless or guilty
Felt anxious, tense, “keyed up” or “on edge”
Had mood swings (eg suddenly felt sad or tearful)
Was more sensitive to rejection or my feelings
were easily hurt
Felt angry, irritable
Had conflicts or problems with people
Had less interest in usual activities
Had difficulty concentrating
Felt lethargic, tired, fatigued, or had a lack
of energy
Had increased appetite or overate
Had cravings for specific foods
Slept more, took naps, found it hard to get up
when intended
Had trouble getting to sleep or staying asleep
Felt overwhelmed or that I could not cope
Felt out of control
Had breast tenderness
Had breast swelling, felt “bloated”, or had
weight gain
Had headache
Had joint or muscle pain
Impairment as demonstrated by interference
with normal work, school or home activities
or interference with usual social activities
and relationships with others
At work, at school, at home, or in daily routine,
at least one of the problems noted above
caused reduction or productivity or inefficiency
At least one of the problems noted above
interfered with hobbies, or social activities
(eg avoid or do less)
At least one of the problems noted above
interfered with relationships with others

Figure 4.2 Daily Record of Severity of Problems.

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

40

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QUANTIFICATION OF PMS AND PMDD 33

Do you experience some or any of the following premenstrual symptoms which
start before your period and stop within a few days of bleeding?
(please print and mark an “X” in the appropriate box)
SYMPTOMS

A. Your work efficiency or productivity
B. Your relationships with co-workers
C. Your relationships with your family
D. Your social life activities
E. Your home responsibilities
Scoring
The following criteria must be present for a diagnosis of PMDD
1. at least one of #1, #2, #3, #4 is severe
2. in addition at least four of #1-#1 4 are moderate to severe
3. at least one of A, B, C, D, E is severe
The following criteria must be present for a diagnosis of moderate to severe PMS
1. at least one of #1, #2, #3, #4 is moderate to severe
2. in addition at least four of #1-#14 are moderate to severe
3. at least one of A, B, C, D, E is moderate to severe

Figure 4.3 Premenstrual Symptoms Screening Tool.

average severity during 7 days.27 The possibility that
different lengths of premenstrual period may be associated with different phenotypes and underlying mechanisms has not been fully elucidated.

DSM-IV allows the diagnosis of PMDD to be made
alongside other disorders, but offers no guidance on
differentiating between the two. The two disorders may
coexist or indeed be intricately related to one another.

In most menstrual cycles during the past year, five (or more) of the following symptoms were present for most of
the time during the last week of the luteal phase, began to remit within a few days after the onset of the follicular
phase, and were absent in the week postmenses, with at least one of the symptoms being either (1), (2), (3),
or (4):
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

markedly depressed mood, feelings of hopelessness, or self-depreciating thoughts
marked anxiety, tension, feeling of being ‘keyed up’ or ‘on edge’
marked affective lability (e.g. feeling suddenly sad or tearful or increased sensitivity to rejection)
persistent and marked anger or irritability or increased interpersonal conflicts
subjective sense of difficulty in concentrating
lethargy, easy fatigability, or marked lack of energy
marked change in appetite, overeating, or specific food cravings
hypersomnia or insomnia
a subjective sense of being overwhelmed or out of control
other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, a sensation
of ‘bloating’, weight gain.

Note: in menstruating females, the luteal phase corresponds to the period between ovulation and the onset of
menses, and the follicular phase begins with menses. In non-menstruating females (e.g. those who have had a
hysterectomy), the timing of luteal and follicular phase may require measurement of circulating reproductive
hormones.
b.

The disturbance markedly interferes with work or school or with usual social activities and relationships with others
(e.g. avoidance of social activities, decreased productivity and efficiency at work or school).

c.

The disturbance is not merely an exacerbation of the symptoms of another disorder, such as major depressive
disorder, panic disorder, dysthymic disorder, or a personality disorder (although it may be superimposed on any of
these disorders).

d.

Criteria a, b, and c must be confirmed by prospective daily ratings during at least two consecutive symptomatic
cycles. (The diagnosis may be made provisionally prior to this confirmation.)

Many of the scales listed in Table 4.1 have been used to
make this distinction, in particular the Beck Depression
Inventory,2 Profile Of Mood States,14 and Hamilton
Depression Scale.1 Other scales which can be administered to assess the woman’s underlying psychiatric
morbidity include the Hospital Anxiety and Depression
Scale,28 General Health Questionnaire,29 SelfReporting Questionnaire, and the Structured Clinical
Interview for DSM-IV (SCID).23
Finally, it is important to reiterate that DSM-IV
PMDD criteria fail to recognize the importance of
physical symptoms, which is unfortunate as most
women will complain of physical symptoms and for
many this will be the most distressing feature. As an
example, a woman with debilitating breast tenderness,
bloatedness, and premenstrual headache with severe
mood swings could be excluded from a diagnosis of

PMDD if she had no other symptoms. More detailed
and precise rating techniques must be devised and the
authors of this chapter have proposed the concept of
Premenstrual Somatic Disorder (PMSD), for which
specific rating scales have been devised but not yet
evaluated or validated.

MENSTRUAL SYMPTOMETRICS
Various researchers have attempted to address the simplification of data collection. One of the simplest was
the Premenstrual Tension-Cator (PMT-Cator), which
was a gadget like an obstetric wheel calculator –
although novel, it was never validated nor used in any
further research. There have been several attempts at
data acquisition, documentation, and transfer into a

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QUANTIFICATION OF PMS AND PMDD 35

database by electronic means. The MiniDoc method
has had limited use; it uses electronic data collection,
but has not been published as a technique. At least one
research study (within a clinical trial) using this technique was terminated prematurely because of difficulties with the system; the authors have been unable to
locate other publications using the technique.
North Staffordshire Hospital/Keele University and
Nottingham University investigated the menstrual
symptometrics device, which was developed and validated against paper-based techniques. This method
used a very early PDA (Amstrad PenPad, which is now
obsolete). Visual analog scales were used to record
scores for symptoms of PMS, dysmenorrhea, and perception of blood loss by means of a ‘pen’ on the touchsensitive screen. It also incorporated the menstrual
pictogram, a previously published pictorial method of
measuring menstrual blood loss volume – hence, all
symptoms related specifically to disorders of the
menstrual cycle could be measured.30
Menstrual symptometrics was a simple ‘palmtop’
personal computer system programmed to collect the
daily menstrual cycle symptoms of PMS, blood loss,
and pain, it was also programmed to include questionnaires to assess the woman’s general health quality of
life using an SF-36 (see next section for description)
and a simple measure of underlying psychological
pathology (General Health Questionnaire, GHQ) were
also documented with other questionnaires incorporated into the system. It avoided the need to measure by
hand the VAS, as the touch-sensitive screen allowed the
instant measuring and storage of scores from VAS. It
had a high level of patient acceptability and could
provide instant pictorial feedback on symptoms for
patients and clinicians.
This method is now obsolete, because of advances in
PDA technology, and the menstrual pictogram is no
longer valid because the blood absorbancy of those
menstrual sanitary products acceptable to most women
has changed dramatically.

MEASURES OF IMPAIRMENT
The measurement of impact or luteal phase impairment
is critical in research and clinical practice if we are to
distinguish PMS/PMDD from what are essentially
normal or physiological symptoms of ovulatory menstrual cycles.
The diagnosis of PMDD also requires the confirmation of luteal phase impairment of social and/or work
functioning. Commonly utilized ratings of role functioning and quality of life reported in prevalence and
treatment studies include the Quality of Life Enjoyment

and Satisfaction Questionnaire (Q-LES-Q), the
Sheehan Disability Scale (SDS), the Short Form of the
Medical Outcomes Study functioning scale (SF-36),
and the Social Adjustment Scale (SAS). The DRSP monitors three functioning items daily that assess impairment at work, school or home; interference with
hobbies or social activities; and interference with relationships with others. Most researchers consider that to
be adequate for most clinical trials.

CONCLUSION
The definitions and diagnosis of PMDD are still fragmented, not widely accepted, and, if accepted, not
always applied in day-to-day clinical practice. We are
still far from a biomedical and/or biopsychological
model of a diagnostic entity based on etiology, pathophysiology, phenomena, time course, and treatment
response.
Methods which use bipolar scores, optimize the
thresholds separating PMS+ from PMS– cycles, and are
based on known PMS symptom patterns are likely to
be satisfactory whatever their level of sophistication.
The vast amount of paperwork involved in recording
a woman’s premenstrual symptoms daily over several
months has meant that the data collection, measurement, and analysis of such data is time-consuming and
labor-intensive, requiring many hours of data acquisition. A personal computer system for data collection
and symptom measurement provides a simplified means
of collecting large amounts of data on a daily basis,
such as measurement of VAS, categorical scores, menstrual icons, and documentation of questionnaires. The
ability to provide a graphic display provides an instant
cyclic image of all the woman’s menstrual cycle symptoms, making diagnosis and appropriate management
of any disorder more accurate and straightforward.
Further studies are needed to validate the possibility
of circumventing the need for prospective daily charting in establishing the diagnosis of PMS or PMDD
possibly by validation of the PSST against the DRSP.
Until an objective means (genetic or magnetic resonance imaging [MRI]) of diagnosing PMS/PMDD is
achieved, diagnosis is likely to rely on daily questionnaires such as the DRSP which most closely relates to
the symptom factors within DSM-IV PMDD, unless of
course the PSST can be shown to be valid. The concept
of PMSD is a new one and, together with new rating
tools, it warrants further exploration.
If such large numbers of data points continue to be
required, electronic methods will increasingly be necessary and are really the only practical way forward. To
consider PMS/PMDD management without reference

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36 THE PREMENSTRUAL SYNDROMES

to other gynecological and psychological comorbidities
is inappropriate. This will need to be taken into
account when these electronic methods are devised.
This chapter gives a summary of techniques and
approaches used over the past 30 years and how we
arrived at where we are today and where PMS/
PMDD/PMSD research may take us in the future. The
milestones are recorded, although it is not comprehensive and is likely to have some omissions. In Chapter 5,
Pearlstein gives further insight into this area of
research, particularly the valuable information that can
be derived from many of the above techniques in relation to investigation, prevalence, and the impact of the
disorder.

PREVALENCE OF PREMENSTRUAL
DYSPHORIC DISORDER
Many studies have examined the prevalence rates of
premenstrual symptoms and premenstrual syndrome
(PMS) in cross-sectional population cohorts and selfpresenting clinical samples. Earlier studies included retrospective reports of PMS, either a ‘Do you suffer from
PMS, yes or no’ or a one-time administered rating scale
of premenstrual emotional, behavioral, and physical
symptoms. The Premenstrual Assessment Form (PAF)1
is one retrospective questionnaire that has been utilized
in some studies. Several studies have suggested that retrospective reporting amplifies the frequency and severity
of premenstrual symptoms. The reasons for the possible
amplification of symptoms are unclear. Symptom severity
peaks on or just before the first day of menses,2–4 and the
reporting of premenstrual symptoms may be influenced
by menstrual cycle phase when questioned, wording of
questions, expectations, and cultural issues.2
Since the introduction of research diagnostic criteria
for premenstrual dysphoric disorder (PMDD) in the
Diagnostic and Statistical Manual of Mental Disorders,
fourth edition (DSM-IV),5 women should prospectively
rate their symptoms daily for two menstrual cycles to
confirm the diagnosis. The prospective charting is
designed to confirm the cyclical nature, timing, and magnitude of the symptoms. Commonly used daily rating
forms reported in prevalence and treatment studies include
the Daily Record of Severity of Problems (DRSP),6 the
Penn Daily Symptom Report (DSR),7 the visual analog
scale (VAS),8 and the Moos Menstrual Distress Questionnaire (MDQ).9 Determination of PMDD diagnosis,
and thus, prevalence rates, can vary, depending on the
scoring method applied to daily ratings. One study
reported a PMDD prevalence rate range of 1–7% in
117 women, depending on the scoring method used,10

and another study reported a range of 14–45% in 670
women, depending on the scoring method used.11
The diagnosis of PMDD also requires the confirmation of luteal phase impairment of social and/or work
functioning. Commonly utilized ratings of role functioning and quality of life reported in prevalence and
treatment studies include the Quality of Life Enjoyment
and Satisfaction Questionnaire (Q-LES-Q),12 the Sheehan
Disability Scale (SDS),13 the Short Form of the Medical
Outcomes Study functioning scale (SF-36),14 and the
Social Adjustment Scale (SAS).15 In addition, the DRSP
monitors three functioning items daily that assess
impairment at work, school, or home; interference with
hobbies or social activities; and interference with relationships with others.
Overall, studies utilizing prospective confirmation of
PMDD, or retrospective assessment of PMDD criteria
suggest PMDD prevalence rates of 3–8% in women
of reproductive age. Recent studies also suggest that
15–20% of women meet criteria for ‘subthreshold
PMDD’ or severe PMS with significant functional impairment. Irritability is consistently reported to be the most
common and severe premenstrual symptom. One study
noted that anxiety, irritability, and mood lability were
the most stable symptoms over several cycles in women
with PMDD, and were the symptoms associated with
functional impairment.16

Prevalence studies using prospectively
confirmed PMDD criteria
Three published studies have examined the prevalence
of PMDD with prospective ratings and have reported
very similar prevalence rates. Rivera-Tovar and Frank
conducted a study in which 217 female college students
(mean age 18.5 ⫾ 1.8 years old) in Pittsburgh,
Pennsylvania rated emotional and physical symptoms

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38 THE PREMENSTRUAL SYNDROMES

prospectively for 90 days.17 Ten women (4.6%) met
criteria for late luteal phase dysphoric disorder, now
called PMDD. Cohen and colleagues reported on the
prevalence of PMDD in 513 women (aged 36–44 years
old) participating in the Boston area community
Harvard Study of Moods and Cycles who rated their
symptoms prospectively using the DRSP for one menstrual cycle.18 The diagnosis of PMDD was confirmed
in 33 (6.4%) of 513 women and was associated with
previous major depressive disorder (MDD), lower education, and current cigarette smoking. Sternfeld and
colleagues reported on the prevalence of premenstrual
symptoms in 1194 women (aged 21–45 years old)
enrolled in a California health maintenance organization who prospectively rated their symptoms for two
cycles using the DRSP.4 Fifty-six (4.7%) met criteria for
PMDD and 151 (12.6%) women met criteria for severe
PMS (defined as meeting PMDD criteria for one cycle
with at least one symptom rated a 5 or 6 in the other
cycle). The prevalence rates in this study may have been
low due to the exclusion of women with known PMDD
or psychotropic medication use. The number and severity of emotional premenstrual symptoms were inversely
related to age and oral contraceptive use, and directly
related to having a medical comorbidity and being
Hispanic relative to being white.

Prevalence studies using PMDD criteria
without prospective confirmation
Wittchen and colleagues published a study that has made
a significant contribution to knowledge about prevalence and comorbidity data in an adolescent community
sample.19 These authors reported the 12-month prevalence and 4-year incidence rates of provisional PMDD
in 1488 women aged 14–24 years old in a community
cohort from Munich, Germany. Although women did
not complete prospective ratings, subjects completed
questions corresponding to the DSM-IV PMDD criteria
relating to the past 12 months, with additional questions about impairment, psychosocial interference, and
the absence of symptoms in the postmenses week. In
addition, comorbid axis I disorders over the previous
year were systematically assessed. At baseline, women
aged 14–24 years old were enrolled, with 14–15 year olds
sampled at twice the probability of 16–21 year olds,
and 22–24 year olds sampled at half this probability.
Follow-up assessments were conducted at approximately
2 and 4 years following enrollment; the age range of the
sample at final follow-up was 18–29 years old.
At least one premenstrual symptom was endorsed by
79.8% of the total sample, with the five most common
premenstrual symptoms being physical symptoms, affect

lability, fatigability, depressed mood, and appetite/
craving. The estimated 12-month prevalence of PMDD
at baseline was 5.8% and the total overall cumulative
incidence up to age 29 years old was 7.4%. When
comorbid MDD and dysthymia were excluded, the
baseline rate dropped to 5.3% and the cumulative
incidence rate to 6.7%. PMDD was stable across the
4 years, with remission occurring in only 4.9%. The
five most common PMDD symptoms were depressed
mood (90.5%), affect lability (89.7%), irritability/
anger (81.5%), fatigability (78.6%), and physical complaints (78.1%). Subthreshold PMDD was found in
18.6% of the total sample at baseline, defined as
meeting most, but not all, of the PMDD criteria. The
most frequent reason for not meeting full PMDD criteria was failure to meet the persistent impairment criterion. The rank order of premenstrual symptoms was
similar for women with subthreshold PMDD but at
lower frequencies compared to women with PMDD.
Both PMDD and subthreshold PMDD groups were
significantly more likely to have a 12-month comorbidity of affective disorder, anxiety disorder, and nicotine
dependence. Unusual findings from this study included
the finding of suicide attempts having occurred in
15.8% of women with threshold PMDD, and significantly elevated 12-month rates of bipolar I, bipolar II
post-traumatic stress disorder (PTSD), social phobia,
and somatoform disorder compared with women without
PMDD. Further analyses of this data have suggested
that previous trauma or an anxiety disorder is associated
with the development of PMDD, while having PMDD
is associated with future episodes of depression.19–21
Steiner and colleagues developed a Premenstrual
Symptoms Screening Tool (PSST) that assesses each of
the PMDD criteria and five questions related to functioning and relationships rated as ‘not at all’, ‘mild’,
‘moderate’, or ‘severe’.22 The PSST was administered to
508 women attending a primary care clinic in Ontario,
Canada. Although prospective ratings and evaluation
of comorbid disorders were not obtained, the PSST
directly inquired about symptoms that started before
the period and stopped soon after menses. Results indicated that 26 (5.1%) women met criteria for PMDD
and 105 (20.7%) women met criteria for moderate–
severe PMS, similar to the results of the Wittchen study
suggesting that approximately 1 in 5 women meet criteria for subthreshold PMDD.
In a cross-sectional telephone survey of 1045 women
in the USA, UK, and France, Hylan and colleagues evaluated premenstrual symptoms based on the DSM-IV
criteria by retrospective report, the extent to which the
symptoms interfered with their home, school, work, or
social life, and treatment-seeking behavior.23 Between
23% and 31% of women were classified as having

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PREVALENCE, IMPACT ON MORBIDITY, AND DISEASE BURDEN 39

severe PMS. The most common symptoms occurring in
about 80% of women in each country were irritability/
anger, physical swelling/bloating, and fatigue. Robinson
and Swindle conducted a cross-sectional survey of 1022
respondents from a nationally representative random
sample of US women, evaluating premenstrual symptoms, social and occupational interference, healthcare
beliefs, and treatment-seeking behavior. The results
reported 11% meeting criteria for PMDD based on the
DSM-IV criteria, and 63% of women having moderate–
severe PMS.24
Prevalence studies in adolescent women with prospective charting of symptoms have not yet been conducted.
Studies utilizing retrospective reporting of PMS have
reported elevated and a wider range of prevalence rates
of PMS compared with adult women. Two recent studies
that retrospectively assessed the PMDD criteria in adolescent women reported prevalence rates of 31%24a
and 13.4%.24b

Prevalence studies using retrospective
PMS criteria
Reviews exist of older published studies of prevalence
rates of PMS.25,26 Some of the studies that were conducted in population cohorts will be mentioned, even
though the studies utilized retrospective assessment of
premenstrual symptoms. Two studies examined the
prevalence of perimenstrual symptoms in a community
cohort of women in Switzerland evaluated five times
over 14 years.27,28 Out of 299 women, 8.1% met criteria for severe, and 13.6% met criteria for moderate,
perimenstrual emotional and somatic symptoms.27 A
study of 894 women in Virginia who were assessed
over the telephone with the MDQ yielded 8.3% having
PMS.29 Severe premenstrual symptoms were endorsed
by 2–3% of 1083 women in Sweden by mail survey.30
Severe PMS with work impairment was reported in
3.2% of 730 nursing students in Iowa utilizing the
PAF.31 Between 2 and 7% of 2650 Canadian women in
a population cohort met criteria for severe PMS by the
MDQ.32 In addition, 3–12% of 191 women in a Seattle
area population cohort reported strong/disabling premenstrual symptoms by the MDQ.33

Prevalence studies in non-US countries
Several studies have examined the prevalence of premenstrual symptoms, PMS, and PMDD in non-US samples.
Studies utilizing prospective confirmation of premenstrual symptoms over one or two menstrual cycles have
reported prevalence rates of severe PMS or PMDD in
18.2% of 384 college students in Pakistan,34 6.4% of

52 volunteer women in India,35 12% of 150 women in
a PMS clinic in Taiwan,36 and 2.4% in 83 women in a
population cohort in India.37 Studies with retrospective
reporting of premenstrual symptoms have also been
conducted in Australia, Brazil, China, Egypt, Finland,
France, Great Britain, Hong Kong, India, Japan,
Mexico, Morocco, Nigeria, Spain, Taiwan, and
Zimbabwe. Cross-cultural comparisons have suggested
a predominance of somatic symptoms relative to emotional symptoms in several ethnic cultures. Caucasian
women endorsed more emotional premenstrual symptoms compared with Afro-Caribbean and Asian subgroups in Great Britain,38 and Australian and Italian
women endorsed more emotional than somatic symptoms compared with Turkish, Vietnamese, and Greek
subgroups in Australia.39

IMPACT OF PMDD ON FUNCTIONING,
QUALITY OF LIFE, AND HEALTHCARE
UTILIZATION
The morbidity of PMDD results from the severity
of the symptoms, the chronic nature of the disorder,
and the resulting impairment in work, relationships,
and activities.40 Halbreich et al estimated that women
with PMDD endure 3.8 years of disability over their
reproductive years based on the global burden of
disease model, similar in magnitude to other major
medical and psychiatric disorders.25 The assessment of
functioning and quality of life is difficult since it incorporates subjective views as well as measurable ratings of
mental and physical health, work functioning, interpersonal functioning, and a sense of well-being.41 In
general, studies of role functioning in women with PMS
and PMDD report greater subjective distress with the
effect of premenstrual symptoms on interpersonal relationships compared to work performance.
In addition to the morbidity and functional impairment from PMDD, healthcare utilization also contributes
to the disease burden. The assessment of healthcare utilization due to PMDD is difficult. Many studies assessing treatment utilization were conducted prior to the
Food and Drug Administration (FDA) approval of selective serotonin reuptake inhibitors (SSRIs) for PMDD in
2000. Even though SSRIs are frequently used for PMDD
currently, the diagnosis code attached to the SSRI prescription (as well as to the visit to the healthcare practitioner) is rarely the code for PMDD; it is more often a
code for depression, anxiety disorder, or a medical condition. Thus, it is likely that prescription rates for
medications for severe PMS and PMDD are largely
underreported. The following summary of studies

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40 THE PREMENSTRUAL SYNDROMES

examines the effect of PMS and PMDD on interpersonal functioning, work functioning, and healthcare
utilization.

Studies with PMS determined by
a single-item question
Outpatient female veterans who endorsed PMS by a
single (yes–no) item (N ⫽ 445) reported significantly
lower SF-36 scores across all domains except energy/
vitality compared with 574 women without any menstrual problems.42 Compared with 26 women who
claimed that they did not have PMS, 26 women who
endorsed PMS had significantly more marital and
family relationship dissatisfaction.43 Another study
reported a lack of absenteeism and objective work
impairment in a group of women who reported having
PMS.44
A random survey study of 220 women who stated
that they had PMS reported that these women felt that
the majority of physicians were not adequately informed
to diagnose and treat them.45 Even though satisfaction
with antidepressants was high, only 15% of women
had tried them. Many women had used vitamin/mineral
supplements, exercise, natural progesterone, and diet
changes in the past year. Phone assessment of a random
national sample of 1052 women resulted in 41% of the
women endorsing PMS.46 Of these women, 42% took
over-the-counter regimens for PMS, primarily analgesics, and only 3% took prescription medications. This
study identified exercise and alternative and homeopathic treatments as also being tried.

Studies with PMS diagnosed by
retrospective survey
Compared with women without PMS, women with
PMS as defined by the PAF demonstrated marital dysfunction in the luteal phase.47 In a population cohort
from Sweden, 10% of 1083 women were unable to
work at least once during the preceding 6 months due
to PMS, and the inability to work was associated with
the severity of emotional and physical symptoms.30,48 In
a survey of 658 women in Britain who stated that they
had PMS after completing a questionnaire derived from
the MDQ, 55% stated that PMS had a major effect on
their relationship with their spouse, 43% stated an
effect with their children, and 33% stated an effect on
their work.49 Almost half of this sample had visited
their general practitioner specifically for PMS over the
past year, and over the previous month 46% had taken
analgesics, 9% had taken vitamins, and 11% had taken
psychotropic medication.

Between 11% and 32% of 310 women were considered to have severe PMS as evaluated by the PAF on a
cross-sectional retrospective survey of 310 women in
general medicine practices in Australia.50 Interpersonal
relationship problems were more frequent than a negative impact on work attendance. Approximately half of
the women had sought help for premenstrual symptoms
and 85% had tried a prescription or over-the-counter
medication. At least one-third of the women had tried
analgesics, rest, exercise, drinking more fluids, vitamins,
and oral contraceptives.

Studies with PMDD diagnosed by
retrospective survey
In the study by Wittchen and colleagues described
above, women with PMDD and subthreshold PMDD
both reported significantly more acute impairment in
their professional and everyday activities over the
preious 4 weeks compared to women without PMDD.19
Both PMDD groups also utilized medical and mental
health practitioners significantly more than women
without PMDD. However, the groups did not differ in
use of psychotropic medication or over-the-counter
preparations for premenstrual symptoms. The results
of this study underscored that significant premenstrual
symptoms, functional impairment, and healthcare utilization occurred in almost 25% of women aged 14–24
years old (combining the provisional PMDD and subthreshold PMDD groups) in a sizeable population
cohort.
In the study by Steiner and colleagues described above,
involving 508 women visiting a primary care clinic, the
administration of the PSST confirmed decreased interest
in work, home, and social activities in 57.7%, 69.2%,
and 65.4%, respectively, of women meeting criteria for
PMDD.22 Decreased interest in work, home, and social
activities was endorsed by 54.1%, 51.0%, and 48.5%,
respectively, of women meeting criteria for moderate–
severe PMS. These results lend further documentation
of the substantial functional impairment in the 21% of
women with severe PMS who do not meet the full
severity criteria of PMDD.22
In the cross-sectional study of 1045 women conducted
in the USA, UK, and France described above, functional
impairment was highest at home; however, 8–16% of
the sample reported missing work in the previous year
due to premenstrual symptoms.23 Approximately 25%
of the women across the three nations had sought
medical help for PMS, non-prescription medication use
occurred in 20–47% of the sample, and prescription
medication use occurred in 3–11% of the sample.
Again, SSRIs had not yet been approved by regulatory
authorities for PMDD at the time of this study.

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PREVALENCE, IMPACT ON MORBIDITY, AND DISEASE BURDEN 41

Symptom severity was associated with impairment in
work functioning and treatment-seeking. The crosssectional study described above of 1022 women randomly assessed in the USA, reported that women who
met criteria for PMDD had interference with all life
domains assessed, particularly relationships, husband,
and children.24 Seeking treatment was associated with
being older, greater severity and frequency of symptoms,
and more positive attitudes toward PMS.

Studies with prospectively confirmed PMDD
A few studies with small samples of women with prospectively confirmed PMS or PMDD have examined work
and family functioning. A study reported increased distress and increased functional impairment, as measured
by the SDS, and reduced quality of life, as measured by
the Q-LES-Q, in 15 women with PMDD vs 15 control
women.51 Another study compared impairment ratings
in 31 women with late luteal phase dysphoric disorder
(now PMDD) vs 34 control women.52 Women with
PMDD reported more negative interpersonal interactions at work, but not more family or work performance problems, compared with women without PMDD.
Family functioning was assessed in 73 women with PMS
and 50 women without premenstrual symptoms.53
Women with PMS reported a higher amount of conflict
in family relationships and more stress in their work
environments compared with non-PMS controls. A group
of 15 women with PMS and their husbands confirmed
a negative effect of PMS on the marital relationship in
another small study.54
Chawla and colleagues conducted further analyses
on the data from 1194 women (aged 21–45 years old)
enrolled in a California health maintenance organization
who prospectively rated their symptoms with the DRSP.55
As mentioned above, 56 (4.7%) met criteria for PMDD
and 151 (12.6%) women met criteria for severe premenstrual syndrome, defined as meeting PMDD criteria for one cycle with at least one symptom rated a 5 or
6 in the other cycle.4 Again, results from this study
reflect women not seeking treatment for premenstrual
symptoms, since women with known PMDD or psychotropic medication use were excluded. This study
assessed work functioning and productivity with the
Endicott Work Productivity Scale (EWPS),56 the roleemotional subscale from the SF-36, and questions
about time missed from work or decreased effectiveness in the past week. In addition, subjects were asked
questions about utilization of medical services, and
psychiatric services, and over-the-counter and prescription medications over the previous week.
As premenstrual symptom severity increased, the
likelihood of emergency room visit, visit with a mental

health clinician, or alternative medicine provider visit
increased. There were no significant differences in healthcare expenditures across the mild, moderate, severe PMS
and PMDD groups in terms of hospitalization rates or
prescription drug utilization. Compared with the
women with minimal PMS, women with PMDD had
significantly more productivity impairment and role
limitation during the luteal phase based on the EWPS
score (p ⬍ 0.01), and the role-emotional score of the
SF-36 (p ⬍ 0.01) and had less effectiveness (p ⬍ 0.01).
Although full-day absenteeism from work was not significantly increased, women with PMDD and severe
PMS reported significantly more hours missed from
work than women with minimal PMS (p ⬍ 0.01).
Borenstein and colleagues examined data from a nonselected cohort of 436 women aged 18–45 years old
enrolled in a medical group with capitated health insurance in Southern California who returned 2 months of
DRSPs.57,58 Approximately 30% of the women met criteria for a diagnosis of PMS in either one or both of the
prospectively measured cycles. Measures of symptoms,
functioning, healthcare utilization, work productivity,
and absenteeism were compared between women with
PMS and women without PMS. However, symptoms
ratings may have been confounded by comorbid psychiatric or medical conditions, and psychotropic medication use, both of which were not systematically
evaluated.
After analysis of the DRSP ratings, 47 women met
criteria for PMS on both cycles, 78 women met criteria
for PMS on one cycle, and 311 women who did not
meet criteria for PMS were considered controls.57,58
Women with one cycle of PMS had statistically significantly lower quality of life as measured by the physical
components summary (p ⬍ 0.0001) and the mental
components (p ⬍ 0.0001) summary measures of the
SF-36 compared with controls.57 Women who met
PMS criteria for both cycles had significantly lower
SF-36 summary scores than women who met PMS criteria for one cycle as well as controls. The magnitude of
the reduction in mental health summary scores for the
women with two cycles of confirmed PMS were comparable or exceeded the magnitude of reductions noted
in studies of patients with depression and chronic
medical illnesses.57 Another study reported on the DRSP
functioning items.58 Women with PMS for both cycles
showed significantly greater impairment than women
with PMS for one cycle and women not meeting PMS
criteria on work, school, and household activities
(p ⬍ 0.0001), social activities and hobbies (p ⬍ 0.0001),
and relationships with others (p ⬍ 0.0001).58
Women who met criteria for PMS for one or both
cycles of PMS had significantly increased work absenteeism, decreased work productivity, and increased

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health provider visits than controls.57 Further analysis
demonstrated that women with PMS were 2–3 times
more likely to miss at least 2 days of work per month
and were 4–6 times more likely to report at least a 50%
reduction in work productivity compared with women
without PMS.58 Women with PMS in both cycles showed
significantly greater decrease in work productivity compared to women with one cycle of PMS and women not
meeting PMS criteria. Women who met criteria for PMS
in one or both cycles were significantly more likely to
use calcium, vitamins, and other non-prescription
medications (p ⫽ 0.02), and to use antidepressants,
antianxiety medications, and other prescription medications (p ⫽ 0.03) for premenstrual symptoms than
controls.58
The largest data available describing the functioning
and quality of life in women with prospectively confirmed PMDD comes from women presenting for multisite clinical trials. Although women with PMDD seeking
treatment may not be the same as women with PMDD
in the community who do not seek treatment, the baseline evaluation of women seeking treatment in these
studies has been systematic and comprehensive. In
addition to baseline assessments, recent treatment trials
have also examined the effect of treatment on functioning and quality of life as secondary outcome measures.

Fluoxetine trials
The largest multisite fluoxetine trial assessed the diagnosis of late luteal phase dysphoric disorder (now PMDD)
with VAS in 313 women.59 In later analyses, 8 items
from the Premenstrual Tension Syndrome – Self Report60
corresponding to work functioning were examined in
304 women.61 At baseline, each of the 8 items were
endorsed by a significantly larger percent of women
during the luteal phase than in the follicular phase (each
p ⬍ 0.001). Both fluoxetine 20 mg daily and 60 mg daily
for 6 months were significantly better than placebo in
improving the 8-item summed score, and the improvement occurred during the first cycle of treatment.
A multisite study compared luteal-phase fluoxetine
20 mg, fluoxetine 10 mg, and placebo in 260 women
with PMDD diagnosed with the DRSP.62 Both 20 mg
(p ⫽ 0.033) and 10 mg (p ⫽ 0.021) fluoxetine for three
cycles were significantly superior to placebo in improving the three DRSP functioning items. Another multisite study compared fluoxetine 90 mg administered 14
and 7 days before expected menses, placebo 14 days
before, and fluoxetine 90 mg 7 days before expected
menses, and placebo both 14 and 7 days before expected
menses in 257 women with PMDD diagnosed with the
DRSP.63 The work, social life, and family life subscales
of the SDS at luteal baseline were 4.8–5.2, 5.2–5.5, and

5.5–6.0, respectively, in the three treatment groups.
The administration of fluoxetine 90 mg twice weekly
before expected menses, but not once before expected
menses, was significantly superior to placebo on improving the work (p ⬍ 0.001), social life (p ⫽ 0.037), and
family life (p ⫽ 0.005) scores of the SDS and the sum of
the three DRSP functioning items (p ⫽ 0.035). A crossover study of flexible-dose fluoxetine and placebo, each
administered for three cycles, in 20 women with
PMDD reported superiority of fluoxetine over placebo
for a composite social isolation and work efficiency
score.64

Sertraline trials
A recent study41 reported on a post-hoc analysis of the
pretreatment Q-LES-Q scores of 437 women with
prospectively confirmed PMDD by DRSP ratings who
had participated in clinical trials of sertraline treatment.65,66 The sum of items 1–14 correlated with the
overall satisfaction and contentment item 16 (r ⫽ 0.78,
p ⬍ 0.0001), suggesting that the broad set of functioning domains assessed by the Q-LES-Q individual items
are related to the overall sense of quality of life. Thirtyone percent of women with PMDD were considered to
have severe quality of life impairment, defined as two
or more standard deviations below the community
norm. Illness-specific symptom measures accounted for
26% of the variance in quality of life for women with
PMDD, suggesting that quality of life assessment should
be part of the diagnostic evaluation and treatment plan
for women with PMDD in addition to specific premenstrual symptoms.41
Three studies have reported on the effect of sertraline
and placebo on the functioning and quality of life in 243
women with PMDD who participated in a multisite
trial of daily flexible-dose sertraline for three cycles.65
Functioning was assessed by the SAS and the three
DRSP items during the follicular and luteal phases at
baseline and during the luteal phase of each treatment
cycle. Quality of life was assessed with the Q-LES-Q at
baseline and during each treatment cycle. The initial
study reported that sertraline was significantly superior
to placebo in improving functioning as measured by the
three DRSP functioning items and the SAS scores.65
Pearlstein and colleagues further examined the data.67
Significant luteal phase impairment was evident compared with the follicular phase during the baseline cycle
on the total and factor SAS scores, and on items 1–14
and the overall assessment score of the Q-LES-Q (all
p ⬍ 0.001). Overall, the luteal impairment noted
with SAS total and factor scores was similar to
cohorts of women with dysthymia, but milder than
women with MDD. Significant improvement with

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PREVALENCE, IMPACT ON MORBIDITY, AND DISEASE BURDEN 43

sertraline compared with placebo was evident by the
second randomized treatment cycle on four of seven
SAS factors, the Q-LES-Q and the three DRSP functioning items. Functional improvement as measured by
the SAS and Q-LES-Q measures correlated with emotional and physical symptom improvement. Women who
remitted (a Clinical Global Impressions-Improvement
score of 1 after three cycles of sertraline treatment) had
significantly higher premenstrual functioning at baseline compared with non-remitters as evidenced by the
SAS total and factor scores, the Q-LES-Q scores, and
the three DRSP functioning items (all p ⬍ 0.001).67
Halbreich and colleagues further compared baseline
luteal SAS and Q-LES-Q scores of this same group of
243 women with PMDD participating in the sertraline
trial65 with baseline measures of women who participated in dysthymia (N ⫽ 175) and chronic MDD (MDD
without remission or MDD and dysthymia, N ⫽ 124)
sertraline trials.25 Again, the pretreatment SAS and
Q-LES-Q scores of women with PMDD and dysthymia
did not significantly differ, except for significantly
worse scores on the parental SAS factor in women with
PMDD. Functional impairment in women with PMDD
was not as severe as women with chronic MDD, overall,
although the parental and social/leisure SAS factors
demonstrated non-significant increased impairment
with PMDD.
Halbreich and colleagues reported on a multisite trial
of flexible-dose sertraline or placebo administered in
the luteal phase over three menstrual cycles in 229
women with PMDD.66 Functioning was assessed by the
SAS and the three DRSP items during the follicular and
luteal phases at baseline and during the luteal phase of
each of three treatment cycles. Quality of life was assessed
with the Q-LES-Q at baseline and during each treatment
cycle. Significant improvement with sertraline compared
with placebo was evident on the total and on four of
seven SAS factor scores, the Q-LES-Q, and the three
DRSP functioning items. The social/leisure and family
unit SAS factor scores significantly improved with sertraline in both the daily dosing and luteal phase dosing
studies.
A study in 167 women compared full-cycle sertraline,
luteal phase sertraline, and placebo for 3 months.68
This study utilized the DSR for prospective confirmation
of premenstrual symptoms; 60% of the 167 women
met strict criteria for PMDD and 40% met criteria for
severe PMS. Global Ratings of Functioning assessed
family life, work, and social activity functioning with
ratings from 0 to 4, with 4 signifying ‘severe disruption’.
The Global Ratings of Functioning scores at baseline
ranged from 2.1 to 2.7 in the 167 women. Results
demonstrated that both dosing regimens of sertraline
were significantly superior to placebo in improving

family relationships and social activities, but not work
functioning.68 An earlier study by this research group
had utilized the DSR, Global Ratings of Functioning,
and the Q-LES-Q in a study comparing full-cycle sertraline, desipramine, and placebo for three cycles.69 In this
study, 74% of 167 women met criteria for PMDD and
26% met criteria for severe PMS. At baseline, the Global
Ratings of Functioning scores ranged from 2.37 to 2.81,
and the Q-LES-Q averaged 45. Sertraline was more
effective than both desipramine and placebo in improving family life, work, and social activity functioning.
Sertraline was also more effective than placebo in
improving quality of life as measured by the Q-LES-Q.

Paroxetine trials
Two multisite studies have been published reporting on
the comparison of daily dosing of paroxetine controlled
release (CR) 25 mg, paroxetine CR 12.5 mg, and placebo
in women with PMDD.70,71 In both studies the diagnosis of PMDD was determined by VAS ratings, and functioning was assessed with the SDS. In the first study,
baseline values of the work, social/leisure, and family
life SDS item scores for the sample of 313 women with
PMDD at baseline were not provided. After three
cycles of treatment, paroxetine CR 25 mg daily was significantly superior to placebo in each SDS domain,
whereas 12.5 mg daily was superior to placebo in the
improvement of social/leisure and family life functioning only.70 In the second study, the ranges of SDS item
scores at baseline in 371 women with PMDD were
work (4.9–5.4), social life (5.7–6.0), and family life
(6.5–6.9). Paroxetine CR 25 mg daily was significantly
superior to placebo in each SDS domain, whereas
12.5 mg daily was superior to placebo in the improvement of family life functioning only.71
A multisite study of the luteal phase administration
of paroxetine CR 25 mg, paroxetine 12.5 mg, and
placebo was conducted in 366 women with PMDD.72
Diagnosis of PMDD was determined by VAS ratings,
and functioning was assessed with the SDS. The total
SDS score ranged from 16.8 to 17.6 in the 366 women
at baseline. Both doses of paroxetine CR were significantly superior to placebo after three cycles of treatment in improving functioning as reflected by
reductions in the total SDS score.

Escitalopram trial
A recent small trial compared luteal phase dosing of escitalopram with symptom-onset dosing of escitalopram
over three cycles in 27 women with PMDD.73 There
was no placebo condition. Diagnosis of PMDD was

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determined by the DSR, and functioning was assessed by
the SDS. The average overall SDS score for both groups
at baseline was 7.25–7.29. The overall SDS score significantly improved at endpoint compared to baseline with
both escitalopram dosing regimens; there was no significant difference between the two dosing regimens.

Oral contraceptive trials
Two recently published studies with a new oral contraceptive containing drospirenone 3 mg and ethinyl estradiol 20 ␮g administered for three cycles have reported
superior efficacy compared to placebo for premenstrual
symptoms, functioning, and quality of life in women
with PMDD.74,75 In both studies, PMDD was determined by prospective DRSP ratings. One of the two
studies was a parallel design study in 449 women. The
DRSP functioning items averaged 3.7–4.2 (out of
maximum possible score of 6) at baseline, and the sum
of Q-LES-Q items 1–14 averaged 57.1–57.9 and overall
life satisfaction score averaged 3.74 The oral contraceptive was superior to placebo for the DRSP items of
improved productivity, enhanced enjoyment in social
activities, better quality of relationships, and items 1–14
of the Q-LES-Q. The second study was a crossover
design study in 64 women. The sum of Q-LES-Q items
1–14 averaged 56.6–59.0 at baseline. The oral contraceptive was superior to placebo for the three DRSP
functioning items (each p ⬍ 0.001), items 1–14, and
the overall life satisfaction item of the Q-LES-Q (each
p ⫽ 0.04).75 Previous studies reported that a similar
oral contraceptive with ethinyl estradiol 30 ␮g improved
premenstrual sense of well-being76 and improved the
ability to perform usual activities as well as well-being
premenstrually in women.77 However, neither of these
two latter studies included a formal assessment of PMS
or PMDD in the samples.
A few small and older treatment studies deserve
mention. An open study of fluvoxamine in 10 women
with PMDD demonstrated a 20% improvement in
Q-LES-Q scores after two cycles of treatment, but this was
not statistically significant.78 A small study comparing 12
sessions of individual cognitive therapy with waitlist in
23 women with prospectively confirmed PMS reported
improvement in total and three SAS factor scores with
cognitive therapy.79 Cognitive therapy did not improve
marital function compared with the waitlist condition, as
measured by a marital questionnaire. A crossover study
comparing luteal phase alprazolam to placebo in 30
women with late luteal phase dysphoric disorder (now
PMDD) reported social dysfunction in 93% and vocational functioning in 59% of women at baseline.80 A significant improvement in premenstrual social functioning
was reported with alprazolam compared with placebo.

PMDD AND ECONOMIC COST OF
DISEASE BURDEN
Borenstein and colleagues attempted to quantify the
direct and indirect costs associated with PMS in the
non-selected cohort of women enrolled in a medical
group who returned DRSPs described above.57,58,81 In
addition to daily ratings of symptoms and functioning
items, women were requested to answer three additional
questions daily:
●
●

●

How many hours did you plan to work today?
How many hours of work did you miss today due to
health reasons?
Please rate your level of productivity at work today.

Direct costs can be assessed by the monetary costs for
clinical visits, hospital care, prescription medications,
laboratory tests, and radiological tests. Indirect costs
can be assessed by work absenteeism and lost productivity at work, or ‘presenteeism’, such as employee errors,
reduced quality, and reduced quantity of work.81
The most recent study from this research group
assessed direct costs by medical claims and indirect
costs by self-reported days of work missed, number of
hours of intended work on a given day, number of
intended work hours missed, and percentage of the total
possible productivity level for the time worked.81 From
data available for 374 women, when women with PMS
were compared to those without PMS, having PMS
resulted, on average, in an additional $59 per patient
per year in direct costs and an increase of $4333 in
indirect costs per patient per year based on a 13.7%
absenteeism rate and a 15% reduction in productivity.
Similar to the economic burden with some chronic
medical disorders, the potential economic impact of
PMS was greater from work productivity losses than
direct medical costs.81
Chawla and colleagues estimated that the cost of
reported lost productivity for 56 women with prospectively confirmed PMDD was $890 per month in the
studies described above.4,55 The authors concluded that
the economic burden associated with premenstrual
symptoms was related more to self-reported decreased
productivity than to direct healthcare costs.

CONCLUSION
Studies of prevalence rates of PMDD suggest 3–8% of
menstruating women meet criteria for PMDD and
15–20% of menstruating women meet criteria for subthreshold PMDD or severe PMS. Several studies suggest
that severity of premenstrual symptoms is associated

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with impairment in functioning, interference with relationships and activities, and decreased work productivity. From the subjective view of women with PMDD,
interpersonal relationship interference is more problematic than work interference. Impaired functioning
significantly affects the group of women with subthreshold PMDD/severe PMS as well as women with
PMDD, expanding the burden of illness to approximately 1 in 5 women of reproductive age. The economic
impact seems to be more severe for the employer than
the health insurer, although prescription rates for
PMS or PMDD are likely to be underreported. The
pronounced negative impact of PMS and PMDD on
quality of life, interpersonal functioning, and work
productivity emphasizes the need for research inquiry
into treatments for this burdensome disorder.

6
Comorbidity of premenstrual syndrome and
premenstrual dysphoric disorder with other
psychiatric conditions
Kimberly A Yonkers and Kara Lynn McCunn

INTRODUCTION
Premenstrual syndrome (PMS) is a relatively common
condition that is experienced by approximately 30% of
reproductive-aged women.1,2 Those with clinically significant PMS regularly experience mood and/or physical
symptoms during the few days to 2 weeks prior to the
onset of menses. By definition, symptoms remit within
a few days after initiation of the menstrual flow, leaving
women asymptomatic for the remainder of the follicular
phase. Common symptoms include low mood, anxiety,
and irritability but physical symptoms such as breast pain
and bloating are also widespread.3 Behaviorally, women
may experience changes in sleep, appetite, energy, concentration, or physical dexterity.
Premenstrual dysphoric disorder (PMDD) occurs in
approximately 3–8% of women,4,5 differs from PMS in
severity, and may diverge in the symptoms experienced.
As with PMS, the diagnosis of PMDD also stipulates
that symptoms are experienced only during the luteal
phase but women must endorse difficulties with at least
one emotional symptom (e.g. low mood, irritability, etc.)6
and symptoms must be severe enough to interfere with
some aspect of psychosocial functioning. The provisional diagnosis of PMDD has been placed in the mood
disorders section of the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition (DSM-IV)
because of the prominent role of mood symptoms in
the condition.6 Criteria for clinically significant PMS7
and PMDD6 stipulate that the temporal pattern of
symptom onset and offset be confirmed through several
months of longitudinal, daily ratings. For both diagnoses, but especially PMDD, symptoms should not be
‘merely an exacerbation’ of another general medical or
psychiatric condition.

Several aspects of the above definitions make it difficult to determine the common comorbidity of PMS and
PMDD. First, it is challenging to conduct epidemiological studies that are representative of general populations when daily ratings are required in order to make
a diagnosis. Completing these reports entails enrolling
subjects who are willing to take on the task of charting
symptoms daily and are compliant with such recordkeeping. Women may not be able to comply for a number
of reasons. For example, it may be that women who are
very symptomatic from either a premenstrual or a
comorbid condition have greater difficulty adhering to
such a task, which would result in biased estimates of
the premenstrual condition. On the other hand, there is
substantial recall bias in reporting premenstrual symptoms,8,9 so, if retrospective reports are used, they may
mischaracterize chronic symptoms as symptoms that
are limited to the premenstrual phase of the cycle.
Secondly, operationalizing what is ‘merely an exacerbation’ of another condition, as stipulated in the DSM-IV
definition, is complex. A woman suffering from a severe
premenstrual condition can experience some symptoms
throughout the menstrual cycle and continue to feel
those symptoms along with additional ones during the
premenstrual phase of the cycle. Whereas some clinicians would say that an underlying disorder is worsened
or exacerbated during the premenstrual phase of the
cycle, others might say that there are two processes
ongoing: a chronic condition and a premenstrual condition.10 These issues are further complicated by the fact
that mood and anxiety disorders are prevalent in women
and peak during the woman’s reproductive years.11–13
Therefore, there is a high likelihood of comorbidity
simply because of the frequency of mood and anxiety
disorders on the one hand and premenstrual syndromes

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50 THE PREMENSTRUAL SYNDROMES

on the other hand. Finally, there are no unique blood
tests or other markers for PMS, PMDD, or indeed any
mood or anxiety disorders. Emotional symptoms of low
mood, disinterest, irritability, and anxiety occur as part
of many mood and anxiety disorders, as well as PMS
and PMDD, and are not unique to any of the various
conditions. The feature that most highly differentiates a
premenstrual condition from other mood or anxiety
disorders is the temporal linkage of symptom expression to the premenstrual phase of the menstrual cycle,
rather than patient characteristics or signs and symptoms. Given these limitations, we organize this chapter
by comorbid condition and provide prevalence estimates
for premenstrual worsening of other psychiatric illnesses as well as lifetime comorbidity. Further, we indicate whether data on comorbidity rely on retrospective
assessments of a premenstrual condition or were made
after completion of daily ratings.

PMDD AND UNIPOLAR DEPRESSIVE
DISORDERS
Women are at approximately twice the risk of developing major depressive disorder (MDD) compared with
men. The National Epidemiologic Survey on Alcoholism
and Related Conditions, a survey of more then 43 000
adults, found that the 12-month prevalence of MDD in
women is 6.87% and the lifetime prevalence 17.10%.14
The high rate of MDD in women increases the likelihood that women with MDD will also have PMDD or
PMS. It is the case that high rates of comorbidity between
either PMS or PMDD and past episodes of MDD have
been documented by a number of groups (see Yonkers,15
Kim et al,16 and Breaux et al17 for reviews). Among
women who have prospectively confirmed PMS or
PMDD and are not in a current episode of MDD,
approximately 30–70% of them will have had a prior
episode of MDD.18–25 Especially if rates are on the higher
end of this range, estimates such as these suggest shared
vulnerability between MDD and PMDD. However, these
estimates are drawn from clinical samples of women
with PMDD rather than non-treatment-seeking individuals and, because patients with a larger number of
psychiatric conditions are more likely to seek treatment,
rates of comorbidity between the two conditions may
be inflated.
Conversely, estimates of concurrent non-seasonal
depressive disorders with PMDD are lower and fall
between 12% and 25%.16 Part of the reason may be that
the symptoms required for the two conditions overlap
and, when an individual is symptomatic and suffering
from MDD, it may be difficult to detect premenstrual
worsening because of a ‘ceiling effect’. Some researchers

who compared rates of concurrent mood disorders in
women who did vs did not prospectively confirm a
diagnosis of PMS or PMDD, find higher rates of MDD
in the latter group although not all studies concur.17,26–28
It is more difficult to detect cyclic symptom changes in
women who have moderate to severe symptoms than in
those who do not. Furthermore, women who retrospectively endorse PMS or PMDD, but do not confirm daily
ratings of symptoms, seem particularly likely to have
MDD or a minor depressive syndrome that accounts
for their complaint. Rather than having comorbid conditions, they may instead misattribute symptoms to the
premenstrual phase of the cycle, when they are, in fact,
chronic. The onset of menses can be a marker that
women may use as a reference point, increasing the likelihood of recall bias. Alternatively, women may have
premenstrual exacerbation of a chronic mood disorder
that might be difficult to fully appreciate as separate
from the underlying condition. Estimates show that up
to 70% of women in clinical cohorts, who have a depressive disorder, also identify problems with premenstrual
symptom exacerbation.29–33 In a recent report, premenstrual worsening of depressive symptoms were retrospectively reported by 64% of a large cohort (n ⫽ 433)
of premenopausal women participating in an antidepressant treatment trial,33 suggesting a substantial clinical
problem.
The comorbidity between seasonal affective disorder
(SAD) and PMDD can be probed by assessing daily
ratings in SAD women during the summer. This sidesteps
potential problems with the ceiling effect, since individuals with SAD are typically not symptomatic during
summer. In one such study,34 46% of women with SAD
but only 2% of healthy controls confirmed symptoms
consistent with PMDD after daily ratings, suggesting a
strong association between the SAD and a premenstrual
disorder.
Symptom deterioration among women with depressive disorders is also found among women who are not
necessarily treatment-seeking. In a comprehensive and
well-designed study, researchers explored premenstrual
exacerbation of depressive symptoms in a community
cohort by examining daily ratings over one to two menstrual cycles.35 The point prevalence for full or subclinical depressive illness in the cohort of women was 6.5%.
Of that group, slightly over one-half (58%) felt worse
premenstrually. The majority of women experienced
deterioration in only one depressive symptom, which
was most commonly sleep (21%) and least commonly
thoughts of death or suicide (2%). Importantly, women
taking antidepressant medication were as likely as those
who were not taking antidepressants to experience premenstrual exacerbation. Given that the medication most
often used to treat depression was a serotonin reuptake

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COMORBIDITY OF PMS AND PMDD WITH OTHER PSYCHIATRIC CONDITIONS 51

inhibitor, medications routinely used to treat PMDD
without comorbid depression, it is clear that other clinical strategies are needed to help women with depression and premenstrual symptom-worsening.
Difficulties with premenstrual symptoms or a premenstrual disorder also predict future episodes of affective illness.36–38 Over time, women with premenstrual
complaints at baseline are more likely to develop new
illness onsets37,38 or recurrences36 of MDD.
It may also be that the types of premenstrual symptoms expressed are influenced by a woman’s vulnerability
to past depressive disorders. Women with prior depression tend to experience time-limited depressive episodes
premenstrually39 rather than other symptom constellations (e.g. anxiety, etc.).40
Investigations of biological processes that are common
to both depressive disorders and PMDD are few. In an
older study that evaluated consecutive cortisol levels
over 24 hours in subjects with MDD, PMDD, and controls,41 subjects with MDD had the highest cortisol levels,
controls had the lowest, and women with PMDD were
in between the two. This suggests some degree of shared
diathesis among women with PMDD and MDD.
In a study that compared plasma -aminobutyric
acid levels (pGABA) in PMDD subjects with and
without a history of MDD, subjects with PMDD and
a history of MDD had low pGABA levels throughout
the menstrual cycle whereas women with PMDD and
no history of MDD had low pGABA only during the
premenstrual phase of the cycle.42 This study suggests
a biological deficit in common between women with
MDD and PMDD, but the deficit only occurs premenstrually if a woman has no comorbid history of
MDD.

PREMENSTRUAL SYMPTOMS AND
BIPOLAR DISORDER
Whereas there appears to be a strong relationship
between unipolar mood disorders and PMDD, the
relationship between PMDD and bipolar disorder is
less clear. Early work that used retrospective reports to
determine premenstrual exacerbation of bipolar disorder suggested higher rates of premenstrual problems
among women with bipolar disorder than controls30,43
or women with other illnesses.44 However, this has not
been confirmed in a study that used prospective ratings
to explore linkages between the premenstrual phase of
the cycle and clinical deterioration.45 In the latter
study, 25 women with rapid cycling bipolar disorder
were assessed over 3–50 months and, although mood
fluctuated over time, it was not more problematic premenstrually.

PREMENSTRUAL SYMPTOMS AND
ANXIETY DISORDERS
Anxiety disorders are quite prevalent, with 28.8% of
Americans experiencing at least one episode of an anxiety
disorder in their lifetime.46 The anxiety disorders include
panic disorder, agoraphobia, social phobia, obsessive
compulsive disorder (OCD), post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder,
and specific phobia. Women are also more susceptible
to these disorders, with an odds ratio of 1.6.46

Obsessive compulsive disorder
Among women attending a PMS clinic, rates for concurrent OCD are three- (9% vs 3%)47 to fourfold higher
(16.1% vs 3.9%)48 than rates of OCD diagnosed in
community women. Diagnoses of OCD in these studies
were generated by structured lay interview but reports
of PMS were based upon retrospective report. However,
these rates are similar (13%) to that found by Fava and
colleagues in a study of women from a gynecological
clinic who kept daily ratings and also underwent a
structured interview.49
Several groups evaluated possible premenstrual worsening or a comorbid premenstrual condition in women
with OCD. These studies typically assessed premenstrual
symptoms in clinical cohorts of women with established OCD.50–52 Premenstrual symptom deterioration
was not uncommon, in that 20–50% of women describe
such difficulties. Differences in these estimates are attributable to instability of figures arising from small cohorts,
differences in questions used to assess premenstrual
symptom worsening, and the retrospective nature of the
reports. In studies that queried women about a spectrum of symptoms, estimates of premenstrual symptom
exacerbation were higher.52 It is interesting that most
symptoms of exacerbation were depression and dysphoria,50,51 although in some instances the underlying
illness of OCD worsened.52 In the recent report by Vulink
and colleagues, a subset of their subjects was assessed
longitudinally across the menstrual cycle and the
symptom scores on the Yale Brown Obsessive Compulsive Scale showed worsening. They found that about
13% of subjects with OCD were comorbid with
PMDD.52 This is a slightly lower estimate of comorbidity with PMDD than found by Williams and Koran
(21%).50

of estimates. Again, using retrospective reports for
PMS or PMDD and structured interviews for panic disorder, between ⬍1% and 9% of women in gynecological settings or PMS clinics also meet criteria for
panic disorder.23,47,48 Interestingly, among women
who prospectively confirm premenstrual difficulties, a
concurrent diagnosis of panic has been found in 16%21
and 25% of women.49
Premenstrual worsening of panic has received considerable study. Several small studies showed that panic
disordered-women commonly reported premenstrual
worsening of panic symptoms but do not confirm such
deterioration with prospective ratings.53–55 These reports
were limited by small sample sizes. A fourth, somewhat
larger, but still modest study found premenstrual worsening of panic among 20 women with panic disorder.56
Interestingly, women with panic disorder experienced
not only worsening of panic attack frequency but also
mood symptoms during the premenstrual phase. The
increased dysphoria experienced by women with PMS
or PMDD study is similar to that noted in studies of
women with obsessive compulsive disorder.52 Mood
symptoms commonly occur with anxiety disorders but
are not criterion items of anxiety disorders. Thus, it is
possible that women with panic or OCD and premenstrual mood symptoms have at least two conditions
contributing to their morbidity: a chronic anxiety disorder and their premenstrual condition.
The relationship between panic disorder and PMDD
has been investigated from a biological perspective (see
Vickers and McNally for a review57). Reproducibly,
women with PMDD have very high rates of panic attacks
after being exposed to a challenge agent. Although
PMDD women do not panic at as high a rate as those
who suffer from panic disorder, rates of panic are higher
than for other psychiatric disorders, including other
mood disorders. To date, research has shown that women
with PMDD are more likely to panic than controls
when exposed to lactate,58–60 carbon dioxide,61 cholecystokinin-tetrapeptide,62 and flumazenil.63 Given that
approximately 50–60% of women with PMDD will
experience a panic attack with these provocative agents,
it has been suggested that there may be shared biological mechanisms in PMDD and panic.62,63 An alternative explanation is that psychological mediators,
including catastrophic misinterpretations of bodily sensations and heightened anxiety sensitivity, in the two
disorders.57

Generalized anxiety disorder
In women who retrospectively reported premenstrual
difficulties, over a quarter also met criteria for generalized anxiety disorder (GAD).47 Studies that included

prospective ratings to confirm premenstrual symptoms
and structured diagnostic interviews find rates of nearly
10%23 and 38%.49 Premenstrual worsening of GAD has
also been reported,64 although how commonly it occurs
is not known.

SCHIZOPHRENIA
Although very rare, periodic psychosis during the premenstruum has been described in numerous case reports
and case series. These reports describe symptoms in adult
women and adolescents that are limited to the premenstrual or menstrual phase of the cycle.65 Some argue that
the low reported incidence is due to under-recognition
of the problem.66 Although the literature does not
support adding psychotic symptoms to the diagnostic
criteria of PMDD, they should be considered a possible
associated feature.65 Routine screening for these symptoms may provide additional evidence for the existence
of premenstrual psychosis.
There have been two prospective studies examining
premenstrual symptom exacerbation in patients with
schizophrenia using the Daily Rating Form (DRF) and
the Brief Psychiatric Rating Scale (BPRS). One study
utilized retrospective and prospective reports of 39
women hospitalized with schizophrenia. The prospective results showed an increase in affective symptoms
during the menstrual but not premenstrual phase. The
retrospective data was collected using the Premenstrual
Affective Form and showed an increase in affective
symptoms in the premenstruum.67 The second study
observed 30 patients with schizophrenia over one menstrual cycle. The data were analyzed for the 24 subjects
who completed the DRF correctly. This study showed
an increase in premenstrual symptoms that were affective and behavioral in nature.68 Neither investigation
found a significant change in psychotic symptoms during
the menstrual or premenstrual phase.67,68 As with a
number of the other comorbid conditions reviewed
above, these reports suggest that women with schizophrenia may experience comorbid PMS symptoms and
‘merely’ premenstrual exacerbation of schizophrenia.
There are observational data that support the theory
of premenstrual exacerbation of schizophrenia. A study
of 285 premenopausal women with schizophrenia
showed that there was an increase in psychiatric admissions during the 3 days before and after the beginning
of menses.69 A smaller study with 33 patients showed
similar results.70 However, these studies did not analyze
which symptoms led to admission, and it is possible
that affective symptoms rendered the baseline psychotic
symptoms even more difficult to tolerate than usual.
Future work may be able to confirm onset of additional

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COMORBIDITY OF PMS AND PMDD WITH OTHER PSYCHIATRIC CONDITIONS 53

symptoms as well as worsening of core schizophrenia
symptoms and resolve this question.

SUMMARY
The most common psychiatric comorbidity among
women with either PMS or PMDD is with other unipolar mood disorders. While this may be because both
types of conditions occur frequently in women, work
suggests shared biological vulnerability. Anxiety disorders are also common, but the relationship between
these conditions and either PMS and PMDD is less well
studied. Interestingly, women with PMDD are at high
risk of panic given the same provocations that lead to
panic in women with panic disorder. Schizophrenia may
worsen premenstrually in some women and isolated psychotic symptoms in the premenstruum are rare but
have been reported.
Identifying comorbidity is important because it may
influence morbidity and treatment. Community studies
show that morbidity is increased when women with
psychiatric illness also have either PMS or PMDD.35
Changes to an agent that is effective for both MDD and
PMDD may be warranted for women who have MDD
and PMDD. Similarly, worsening of mood symptoms in
a woman with schizophrenia while she is premenstrual
may require addition of an agent to treat the premenstrual condition. The existence of concurrent PMDD
should be explored in women who have other psychiatric illnesses that do not respond to usual treatments,
since this can be a source of non-response.

INTRODUCTION
The premenstrual syndromes (PMS) are characterized
by symptoms that are limited to the luteal phase of the
menstrual cycle, occur for several days to 2 weeks before
menses, and remit during the menstrual flow. Over 300
symptom complaints have been linked to the condition.1 Although a diagnosis of PMS is clearly hampered
by the absence of a biological marker, the more immediate problem is the absence of accepted, evidence-based
diagnostic criteria to evaluate the numerous undifferentiated menstrual cycle complaints that may be presented
to the clinician. This chapter addresses the clinical presentation and course of premenstrual symptoms, the
current diagnostic criteria, and considerations in evaluating premenstrual symptoms of women who seek
medical treatment for PMS.

NOMENCLATURE OF PMS
The term PMS as used by both clinicians and the general
public is generic, imprecise, and commonly applied to
numerous symptoms that range from the mild and
normal physiological changes of the menstrual cycle to
clinically significant symptoms that limit or impair
normal functioning. When the severity of the symptoms
is not identified, up to 90% of menstruating women report
PMS symptoms.2,3 Only a small minority of women
report severe premenstrual symptoms that impair functioning. Three to eight percent of women meet the
stringent criteria for premenstrual dysphoric disorder
(PMDD), a severe dysphoric form of PMS.4–6 In addition to the number of women who meet criteria for
PMDD, another 19–21% of women may be only one
symptom short of meeting the PMDD criteria as identified in both a population-based study and a clinical

study of women seeking treatment for premenstrual
symptoms.4,5 These results are consistent with epidemiological studies that have identified approximately 20% of
women with moderate to severe PMS.5,7,8 In this chapter,
the term PMS is used to indicate a clinically significant
disorder that affects approximately 20% of menstruating
women in addition to those diagnosed with PMDD.

PMS SYMPTOMS
Numerous symptoms have traditionally been attributed to PMS. The symptoms are diverse and range over
mood, behavioral, cognitive, autonomic, allergy, gastrointestinal, fluid retention, and pain domains. Many
healthy women describe premenstrual symptoms but
view them as normal and not troublesome.9 The plethora
of over 300 premenstrual complaints is due in part to
the absence of a clear diagnosis that distinguishes
PMS from either normal or other comorbid conditions.
Numerous physical and psychiatric disorders are exacerbated premenstrually or occur as a comorbid disorder with PMS.10
When a careful diagnosis is made to distinguish PMS
from other conditions, a much smaller group of symptoms
appear to be typical of the disorder. Among women who
have been screened for PMS, mood and anxiety symptoms are the primary complaint (irritability, anxiety,
tension, mood swings, feeling out of control, depression) and account for much of the functional impairment.11 Other symptoms usually accompany the mood
symptoms, most commonly behavioral symptoms such
as decreased interest, fatigue, poor concentration, and
poor sleep and physical symptoms such as breast tenderness and abdominal swelling.
There is no consensus on the key symptoms of PMS
or whether there are core symptoms that define the

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56 THE PREMENSTRUAL SYNDROMES

clinical syndrome. There is some evidence that irritability and tension are the cardinal symptoms of PMS.8,12,13
Depressive symptoms such as low mood, fatigue,
appetite changes, sleep difficulties, and poor concentration are also frequent complaints of women with PMS.
While these are symptoms of anxiety and depressive
disorders, studies in recent years have provided strong
evidence that severe PMS is a distinct disorder and not
a simple variant of either depression or anxiety.14,15
Such evidence includes:
1.

2.

3.

4.

5.

6.

7.

The rapid response to selective serotonin reuptake
inhibitors (SSRIs) within hours or a day or two, as
demonstrated by the efficacy of luteal phase dosing,
rather than the 1–4 weeks that may be required for
depression.12,16,17
The maximal response of PMS patients to SSRIs at
low doses, with little or no additional improvement at the high end of the dose ranges, which
may due to factors other than the inhibition of 5hydroxytryptamine (5-HT) reuptake that is believed
to improve major depressive disorder.18,19
The predominance of irritability symptoms
together with physical symptoms such as breast
soreness and swelling, symptoms that are not characteristic of depression but respond to SSRI treatment for PMS.16
The lack of association between the response to
SSRIs and a history of depression or depressive
symptoms in PMS patients.20,21
The positive response of PMS patients to
gonadotropin-releasing hormone (GnRH) agonist
treatment, which is not effective for depressive
disorders,22,23 and the poor response of PMS
patients to the antidepressant bupropion or to most
tricyclic antidepressants, which have less selective
serotonergic activity but are very effective for depressive disorders.20,24–26
The chronic course of PMS, which is unlikely to
remit without treatment and appears to have
swift return of symptoms after discontinuation of
medication.4,27–30
The positive response of PMS/PMDD patients to
panic provocation in laboratory studies, but
neither a history of panic disorder nor a biological
abnormality shared with panic disorder patients
has been identified.15

Prevalence
Surveys indicate that premenstrual syndrome is among
the most common health problems reported by women of
reproductive age.31 Current estimates of the prevalence

of severe PMS range from 12.6% to 31% of menstruating women.5 The severe, dysphoric form, termed premenstrual dysphoric disorder, is limited to 5–8% of
menstruating women.4 In another community-based
study, 8% of menstruating women had severe premenstrual symptoms and 14% had moderate premenstrual
symptoms that were significantly associated with functional impairment.8 Using PMDD criteria to define cases
in population-based data indicated that, in addition to
the 5–8% who met criteria for PMDD, another 18%
were only one symptom short of the five symptoms
required for the diagnosis.4 These estimates consistently suggest that approximately 20% of women experience premenstrual symptoms that are severely distressing
or impair functioning and are consistent with the
numbers of women who believe they need treatment
for PMS as reported in other survey studies.3,32–34

COURSE OF PMS
PMS is a chronic disorder that occurs in ovulating
women. The symptoms appear to gradually worsen with
age until ovarian activity declines and ultimately ends
at menopause. In a population-based study, severe
PMS was highly stable over time, and full remissions of
untreated cases were quite rare.4 A recent follow-up
study of PMS patients likewise found that the symptoms of women with untreated, clinically significant
PMS were stable across menstrual cycles.11
The peak symptom levels of PMS in our clinical
samples occur between the late twenties and late thirties.
The mean age in these samples is in the early thirties
and seldom includes adolescents.35 The mean age at
onset of PMS is around 26 years old, as reported by the
women in clinical treatment samples, but the wellknown biases of recall must be considered in these
retrospective reports.36
In contrast, population-based data from adolescent
women (aged 14–24 years old) indicate that 5.8% of
these young women met criteria for PMDD and an
additional 18.6% were ‘near threshold cases’.4 These
estimates strongly suggest that severe PMS starts in the
teen years and early twenties. It is noteworthy that this
proportion appears to be similar across the reproductive years, as indicated in another population-based
sample of women aged 36–44 years old, where 6.4%
had a confirmed diagnosis of PMDD, only slightly more
than the 5.8% with PMDD among women aged 14–24
years old.6
PMS is understood to occur in ovulatory menstrual
cycles, and therefore ends with the cessation of ovulation at menopause. Clinical data show that the overall
severity of PMS decreases in the fifth decade, possibly

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CLINICAL PRESENTATION AND COURSE OF PMS 57

because ovulation is less frequent as women enter the
menopausal transition.35 These findings were supported
in a population-based cohort study of women who
reported that their PMS symptoms significantly decreased
after age 40 years old.37 New symptoms that occur in the
transition to menopause may be difficult to distinguish
from those of PMS/PMDD. Another study found that a
higher-than-expected percentage of perimenopausal
women with an onset of depression also had premenstrual dysphoria.38 Several studies have shown that
women with a history of PMS were more likely to experience symptoms in the transition to menopause that
were not limited to the luteal phase of the menstrual
cycle, particularly hot flashes, depressed mood, poor
sleep, and decreased libido.37–39

PMS AND DIAGNOSTIC CRITERIA
The diagnosis of PMS continues to lack widely
accepted criteria and remains controversial, in spite of
the many women who seek medical treatment for the
disorder.31,32 At this time, three proffered diagnoses
differ considerably in their criteria and utility for assessment in clinical practice.
The WHO International Classification of Diseases, 10th
edition (ICD-10) lists premenstrual tension syndrome
(PMTS) as a gynecological disorder.40 This diagnosis
requires no specific symptoms or number of symptoms,
and provides no requirement for level of severity, differential diagnosis, or exclusion criteria, resulting in no
systematic criteria for PMS. The non-specificity of this
diagnosis is consistent with the view that there are over
300 premenstrual complaints associated with PMS but
fails to differentiate severe PMS either from normal
premenstrual changes or from other psychiatric or
physical disorders with similar presenting complaints.
In contrast to the non-specificity of the ICD-10
diagnosis of PMTS, criteria for a severe, dysphoric
form of PMS, termed premenstrual dysphoric disorder,
were included for further research in the Diagnostic
and Statistical Manual of Mental Disorders, 4th edition
(DSM-IV).41 The PMDD criteria require five of 11 specified symptoms at a severe level in the premenstrual
phase of the cycle, symptom remission in the follicular
phase of the cycle, marked functional impairment,
absence of other diagnoses that would account for the
symptoms, and prospective confirmation of the symptoms for at least two consecutive menstrual cycles.
The symptoms included in the PMDD diagnosis are
depressed mood, anxiety/tension, mood swings, anger/
irritability, decreased interest, difficulty concentrating,
fatigue, appetite changes, sleep difficulties, feeling out of
control, and physical symptoms. Of the five symptoms

required to meet the PMDD criteria, at least one must
be among the first four emotional symptoms listed above,
and all physical symptoms, regardless of the number, are
considered a single symptom for meeting the diagnostic
criteria.
The PMDD criteria have been used by many
researchers in recent years. These criteria mark a major
step in providing specific parameters for a diagnosis of
premenstrual symptoms, and the use of PMDD criteria
has contributed to identifying effective treatments and
increasing scientific information about the disorder.
However, the clinical application of the PMDD criteria
is limited by its psychiatric focus and complexity and
only a small minority of women who seek treatment
for premenstrual symptoms meet the PMDD criteria.
Moreover, there is no data-based evidence for the
assumptions of the diagnosis, and responses to treatment do not differ between women diagnosed with
PMDD and women who do not meet the PMDD criteria
but have severe PMS.20,21
In contrast to the psychiatric emphasis of PMDD, a
third diagnostic approach was recently offered by the
American College of Obstetricians and Gynecologists
(ACOG).42 The ACOG criteria for PMS require only
one of 10 specified symptoms during the 5 days before
menses, remission during the menstrual flow without
recurrence of the symptoms until at least cycle day 13,
identifiable impairment or distress, absence of other
diagnoses that would account for the symptom(s), and
prospective confirmation of the symptom(s) for three
menstrual cycles.
The symptoms included in the ACOG criteria are
depression, angry outbursts, irritability, anxiety, confusion, social withdrawal, breast tenderness, abdominal
bloating, headache, and swelling of extremities.
The ACOG criteria avoid the symptom count required
for the PMDD diagnosis and instead emphasize overall
severity as demonstrated by distress or impaired functioning. As with the PMDD and ICD-10 criteria, the
extent to which these criteria appropriately diagnose
women who seek treatment for PMS has not been
demonstrated.
Each of these three diagnoses attempts to provide
parameters for a diagnosis of PMS. Importantly, all
lack a standard approach to operationalizing their proposed criteria. The severity of the symptoms, the degree
of distress or interference with functioning, and the
predominant symptoms of the patient’s complaint can
vary widely depending on the methods applied to operationalize the diagnostic criteria. This was demonstrated in a recent study, which showed that the method
selected to determine severity thresholds for PMDD
resulted in widely divergent samples.43 The study also
showed that the interference criterion contributes little

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58 THE PREMENSTRUAL SYNDROMES

to the diagnosis of PMDD, in part due to the high correlation between symptom severity and self-reported
impairment.

PMS symptoms and assessment tools
PMS is diagnosed on the basis of the timing and severity
of the symptoms and the degree of distress or functional impairment. PMS symptoms must be limited to
the luteal phase of the menstrual cycle and subside
during the menstrual flow. These factors, together with
an assessment of whether other physical or psychiatric
disorders may account for the symptoms, are more
important for the diagnosis than the particular symptoms, which are typically non-specific and must be
assessed for their relationship to the menstrual cycle.
Most women who seek medical treatment describe
multiple symptoms, with the primary symptoms and
most distressing problems usually focused on the mood
and behavioral symptoms. Physical symptoms are
widely experienced by women around menstruation,
but many women do not perceive problems with these
symptoms. Physical symptoms alone in the luteal phase,
without other mood or behavioral symptoms, are
seldom sufficient for a clinical diagnosis of PMS. Physical
symptoms, particularly pain around menses, often point
to primary dysmenorrhea or endometriosis, which are
distinct and a separate diagnosis from PMS.
Referral patterns can influence the diagnosis.
Gynecologists may focus on the physical symptoms
that are associated with the menstrual cycle, while
psychiatrists may focus on the mood problems. Patients
who have severe psychological problems may go to
gynecologists rather than psychiatrists in order to avoid
the label of a psychiatric illness.
The pattern of luteal phase symptoms that remit during
menses is clearly demonstrated with daily symptom
reports from PMS patients charted over the menstrual
cycle.44,45 The effect size of the overall symptom scores
compared between PMS patients and normal controls
for each day of the menstrual cycle exceeds 1.6 from
approximately cycle day 17 through cycle day 1.45 It is
important to note the magnitude of this difference
between PMS patients and non-patients in the most symptomatic time period. Women, overall, report increasing
symptoms in the week before menses and decreasing
symptoms in the week following day 1 of menses,45,46
but the severity of the symptoms in women with PMS
significantly exceeds the symptom levels of women
without PMS.
The key diagnostic tool for evaluating premenstrual
symptoms is the daily symptom report. The criteria for
PMDD and the ACOG PMS diagnosis require that the
reported symptoms are confirmed and linked to the

menstrual cycle in the requisite pattern by the prospective daily symptom reports maintained for at least two
menstrual cycles. Numerous daily symptom reports
that are appropriate for the diagnosis of PMS are identified in the literature47 (see Chapter 4). No one of these
forms is considered the ‘gold standard.’ Rather, it is
important to select a symptom rating form that includes
the symptoms required for the target diagnosis (e.g.
PMDD) and will encourage compliance of the patients.
It is also important that the rating scale is sufficient to
indicate the severity of each symptom and not simply
an indication of their presence or absence.
Steiner et al developed a simple questionnaire to use
at the office visit, named the Premenstrual Symptoms
Screening Tool (PSST) for clinicians.48 Use of this form
successfully identifies PMDD patients and suggests the
utility of a brief retrospective report of PMS symptoms,
although its validation against prospective daily reports
is needed. The daily rating form that has been used most
frequently in studies of PMDD is the Daily Record of
Severity of Problems (DRSP).49 Other forms that were
designed to assess PMS/PMDD and have been used in
multiple research studies include the Daily Symptom
Report (DSR), the Calendar of Premenstrual Experiences
(COPE), and visual analog scales where the selected
symptoms are each rated on a line that represents a
linear scale.45,50,51
The primary reason for obtaining prospective information about the symptoms is that many women who
state they have PMS fail to confirm the required pattern
when they report their symptoms daily. Consequently,
daily symptom reports have become a requirement in
research studies, although clinicians frequently avoid
their use, in part because they are cumbersome and timeconsuming for both the patient and the clinician.
Rating symptoms for several menstrual cycles also delays
the initiation of therapy, which some patients are unwilling to accept. Nonetheless, daily symptom reports provide
diagnostic information and are particularly helpful in
pointing to other problems when the reports show that
symptoms occur randomly or throughout the menstrual cycle. When there is evidence that symptoms are
not limited to the luteal phase of the cycle, it is likely
that other medical or psychiatric problems are present,
and treatment of PMS alone will be inappropriate and/or
ineffective.
The daily symptom reports are also an important educational tool for patients. By systematically recording
their symptoms, many women learn to recognize their
symptom patterns over the menstrual cycle, confirm
for themselves whether they do or do not have PMS,
and gain an increased sense of control in managing their
symptoms. During this diagnostic interval before initiating drug treatment, patients can also be encouraged

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CLINICAL PRESENTATION AND COURSE OF PMS 59

to try self-help strategies that are widely recommended
for PMS to determine whether a non-medical approach
is helpful.52

Diagnostic procedures
There are no laboratory tests or physical findings that
indicate a diagnosis of PMS. Laboratory tests should
not be routinely performed for this diagnosis, although
laboratory tests that indicate or confirm other possible
disorders are useful if suggested by the individual woman’s
symptom presentation or medical findings. A gynecological examination is not mandatory, but may be important for ruling out other disorders. Patients may consider
a pelvic examination unnecessarily intrusive, particularly in the absence of physical symptoms. Menstrual
cycles that are irregular or outside the normal range are
an indication for further gynecological evaluation.
Specific information on functional impairment is helpful
for determining the impact of the symptoms. A medical
history with emphasis on reproductive events, other
physical disorders that might account for the symptoms, mood disorders, and family history of PMS and
mood disorders should be obtained.

Premenstrual exacerbations and
comorbidities
Other disorders need to be identified if present. Primary
dysmenorrhea is often confused or included with PMS
but is a distinct diagnosis. Dysmenorrhea is characterized by pelvic pain or backache that may occur for several
days but typically peaks on the first day of the menstrual
flow. Primary dysmenorrhea is linked to prostaglandins
originating in secretory endometrium and is relieved by
prostaglandin inhibitors in the great majority of dysmenorrheic women. Pelvic pain, backache, or complaints
of dyspareunia may also signal endometriosis, particularly in women who previously had pain-free menses for
an extended period of time. Symptoms of endometriosis can be present throughout the month and are not
limited to the luteal phase, although women can also
have extensive endometriosis with little or no pain.
Migraine is associated with ovulatory cycles, as indicated
by its onset at menarche (10.7%), attacks in the time
around menses (60% of cases), and disappearance
during pregnancy (67% of cases), and may be a modulator of PMS.53,54 Menstrually related migraine attacks
appear longer and less responsive to the treatments
than non-menstrual attacks and consequently may
require different treatment considerations.55
Many women who seek treatment for PMS have a
depression or anxiety disorder that is exacerbated premenstrually.56,57 The extent of premenstrual exacerbation

is suggested in the large STAR-D study of major depressive disorder, where 64% of the premenopausal women
not taking oral contraceptives reported premenstrual
worsening of their depression.58 The mood symptoms
that are predominant in PMS include depression,
anxiety, tension, and irritability, but these symptoms
are ongoing in mood and anxiety disorders and are not
limited to the luteal phase of the menstrual cycle. One
approach to differentiating PMS and mood disorders is
to evaluate the patient at least once in the postmenstrual phase of the cycle when premenstrual symptoms have remitted. Clinically significant mood or
anxiety symptoms in the postmenstrual phase strongly
suggest a psychiatric or other medical diagnosis.
There are numerous other conditions whose symptoms may be confused with PMS or may be exacerbated premenstrually. Physical conditions such as uterine
fibroids, endometriosis, adenomyosis, chronic pelvic
pain, ovarian cysts, pelvic inflammatory disease, seizure
disorders, thyroid disorders, asthma, allergies, diabetes,
hepatic dysfunction, lupus, anemia, chronic fatique syndrome, fibromyalgia, and infections may worsen premenstrually. Other psychiatric conditions that may be
comorbid or exacerbated premenstrually include substance abuse, eating disorders, and schizophrenia. It
can be difficult to determine whether the symptoms
are an exacerbation of a comorbid condition or PMS
symptoms (that occur only in the luteal phase) superimposed on another condition. In either case, the usual
recommendation is to treat the underlying condition
first, then assess the response to treatment and possibly
increase the dose premenstrually and/or add medication for the symptoms that arise in the premenstrual
phase.

SUMMARY
Guidelines and criteria for diagnosis of PMS have
advanced in the past decade. Appropriate diagnosis has
become increasingly important as effective treatments
have been identified for PMS, and the majority of patients
can obtain relief from their symptoms. However, it is still
difficult for primary care clinicians to evaluate a disorder
that is linked with hundreds of possible symptoms, lacks
widely accepted criteria, and depends upon the patient’s
maintaining daily reports of the symptoms for several
months. A greater consensus on the diagnostic criteria
for PMS is needed, together with an empirical demonstration that the criteria appropriately diagnose women
who seek treatment for PMS. Further studies of the utility
of well-designed retrospective reports of the symptom
complaints that can be administered at the office visit
are also needed. Continued advances in the diagnosis of

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PMS will contribute to reducing the healthcare costs
that are incurred by the large numbers of women who
seek medical care for this distressing disorder.

INTRODUCTION
Ovulatory menstrual bleeding can be considered the
final curtain call on a precisely choreographed play that,
each month, sees hypothalamic, pituitary, and gonadal
hormones interact in an effort to optimize circumstances
for reproduction. In non-contracepting women, when
not interrupted by pregnancy or lactation, this play can
be expected to run for some 40 years.
Estimates suggest that a century ago women would
experience fewer than 100 menstrual cycles in a lifetime
because of repeated interruptions for pregnancy followed
by lengthy intervals of breast-feeding. In contrast, today’s
woman can expect to experience many more menstrual
cycles in her lifetime in part due to earlier menarche,
later menopause, and widespread use of effective contraception resulting in fewer pregnancies.
The fetal ovary is reported to contain some seven
million germ cells in the fifth month of gestation. Most
of these are lost before birth, with the newborn female
having only 1–2 million oocytes remaining. By puberty
the number of oocytes has dropped to 500 000 and it is
from this pool that one egg matures and an additional
1000 oocytes are lost each month until the oocyte pool
is ultimately depleted and menopause begins.1,2 In the
final 5 years before menopause the remaining oocytes
show increasing resistance to gonadotropic stimulation,
resulting in menstrual cycles which are irregular, unpredictable, and punctuated by transient signs and symptoms of menopause. Although the phase from menarche
to menopause is often referred to as ‘the reproductive
years’ it is now clear that the competence of oocytes
declines steadily with age and that pregnancy is an
uncommon event after age 40 years old. In the absence
of contraception or other endocrine disruption to menstrual cyclicity (e.g. excessive weight loss or gain, thyroid
dysfunction, hyperprolactinemia, etc.), the modern
woman can expect to have 400–450 menstrual cycles in
her lifetime.3

PUBERTAL ONSET OF HYPOTHALAMIC
ACTIVITY
The hypothalamic decapeptide gonadotropin-releasing
hormone (GnRH) regulates the synthesis and secretion
of the pituitary gonadotropins – luteinizing hormone
(LH) and follicle-stimulating hormone (FSH) – that are
ultimately responsible for ovarian activation. A hypothalamic ‘pulse generator’ regulates the pulsatile release
of GnRH. Throughout childhood, central mechanisms
block the release of GnRH. Typically around the age of
11 or 12 years old, this central restraint declines – initially
resulting in nocturnal pulses of GnRH and ultimately
in 24-hour GnRH pulsatile secretion. These GnRH
pulses, in turn, lead to pituitary release of LH and FSH
and subsequent activation of ovarian steroidogenesis.4
Kisspeptins (named for the famous Hershey ‘kiss’
chocolate produced in the place of their discovery –
Hershey, Pennsylvania) represent the most exciting new
research development in our understanding of puberty.
The kisspeptins are a family of proteins derived from
the metastasis repressor gene which are ligands for
GPR54, a G-protein receptor.5 Mutation in this receptor
has been found in humans with delayed puberty and
hypogonadotropic hypogonadism.6,7 Administration of
kisspeptin-10, the most potent ligand of GPR54,
advanced pubertal onset in female rats and stimulated
GnRH secretion in peripubertal non-human primates.7,8
Metastasis repressor gene and GPR54 gene expression
is increased in the hypothalamus of female peripubertal
monkeys.9 Together, these findings are strong evidence
that GPR54 signaling is critical to the initiation of puberty.

OVARIAN STEROIDOGENESIS
A ‘two cell – two gonadotropin’ hypothesis has allowed
a better understanding of the changing steroidogenesis
that results during the menstrual cycle (Figure 8.1).

Under the influence of LH, the well-vascularized
theca cells synthesize androstenedione and testosterone.
These androgens diffuse through the basement membrane of the follicle to reach the avascular granulosa
cell layer where they form the substrate for estrogen
production.10
FSH exerts its effects primarily on the granulosa cells
that line the inside of the antral follicle, causing (1)
mitosis and a rapid increase in granulosa cell numbers,
(2) an increase in cell surface FSH and LH receptors,
and (3) the acquisition of aromatase activity by granulosa cells.11 As aromatase within this follicle converts
androgens to estrogen, estrogen is released into the circulation and exerts negative feedback at the hypothalamus and pituitary to inhibit FSH secretion. As the
menstrual cycle progresses, there is gradual reduction in
FSH release. Each of these effects is critical to the process
of achieving monofollicular ovulation in primates.
Follicular growth starts out as an FSH-independent
process. Primordial follicle development is slow and
highly variable, at times taking 120 days to develop into
2 mm preantral follicles. This process is almost certainly regulated by intraovarian peptides in a paracrine
fashion.10 The final 15 days of follicular growth depends
on a cyclical rise in FSH.

Follicular development in this final stage (representing
the ‘follicular phase’ of the menstrual cycle) has been
divided into three stages: ‘recruitment’, ‘selection’, and
‘dominance’. The phase of ‘recruitment’ starts a day or
two before menstruation and concludes by day 4 of the
follicular phase. The onset of this phase is initiated by
the demise of the corpus luteum from the preceding
cycle. The hypothalamus and pituitary are released
from the restraining effects of progesterone and inhibins produced within the corpus luteum, resulting in a
rapid rise in FSH and the ‘recruitment’ of a new cohort
of antral follicles to enter the maturation process. By
day 5, one follicle from this cohort starts to gain a competitive advantage over the other recruited follicles.
Which follicle will be selected is probably more a matter
of chance than of destiny. Analogous to pups around a
food bowl – one pup, by chance, gets slightly larger than
the others. This results in a competitive advantage that
allows that pup to continue to gain over its litter mates.
As one follicle gets a slight ‘head start’ in its growth it
becomes slightly more sensitive than neighboring follicles to FSH. Its competitive advantage comes from the
fact that it releases into circulation increasing amounts
of estrogen, that in turn suppresses the pituitary release
of FSH needed to allow continued growth of smaller

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PHYSIOLOGY OF THE MENSTRUAL CYCLE 65

follicles in the cohort. Since the slightly larger follicle
has acquired more granulosa cells, more FSH and LH
receptors, and more aromatase activity, it is better able
to survive the falling FSH levels. Recent evidence indicates that FSH and LH receptors share a common
intracellular cyclic AMP pathway; hence, the ‘selected’
follicle can develop in response to either FSH or LH,
unlike smaller follicles in the cohort, which have few
LH receptors. For the remainder of the cohort, the drop
in FSH at such an early stage in development results in
their gradual demise by day 8 of the cycle. At the same
time, the selected follicle appears to release certain proteins that have paracrine effects. Vascular endothelial
growth factor (VEGF) results in an increased density of
capillaries around the dominant follicle and thereby
enhances delivery of FSH, LH, and steroidogenic substrates necessary for final development of the dominant
follicle.10 Ultimately, this ‘dominant’ follicle undergoes
exponential growth over the final 5–6 days of the follicular phase, culminating in ovulation around day 14.

serum LH concentration. Granulosa cells are decidualized by high concentrations of LH and acquire the
ability to produce progesterone. After ovulation, this
production of progesterone by the corpus luteum influences opioidergic, noradrenergic, and -aminobutyric
acid (GABA) systems within the hypothalamus, slowing
GnRH pulse frequency to one pulse every 3–5 hours.18
Corpus luteal production of estradiol and inhibin A
reduces FSH release into the circulation, resulting in
accumulating pituitary stores of FSH. When the corpus
luteum eventually undergoes demise, the subsequent FSH
release starts recruitment of a new cohort of follicles.19
LH pulses (as a marker for GnRH pulse frequency) have
been examined through frequent sampling of blood at
different phases of the menstrual cycle in women with
premenstrual syndrome (PMS) and controls, with no
significant differences being detected.20

INTERPLAY BETWEEN OVARIAN AND
PITUITARY HORMONES

The menstrual cycle is typically described in two
phases: the follicular phase, a 10–14 day period leading
up to ovulation; the luteal phase, the 12–14 day phase
from ovulation until the onset of menstrual bleeding
(Figure 8.221). Low levels of estradiol are present from
immediately prior to menstrual bleeding until the dominant follicle begins to grow.
Late in the second week of the menstrual cycle, estradiol concentrations reach approximately 1000 pmol/L.
Coincident with follicular rupture, there is a transient
but abrupt fall in estradiol levels for a 24–48-hour
period. This abrupt midcycle drop in estradiol has been
associated with endometrial destabilization and bleeding
in some women22 and transient PMS-like mood symptoms in others.23 Ovulatory pain has been termed ‘mittelschmerz’ while the periovulatory mood disturbance
is recorded as ‘mittelwahn’ in the older literature on
PMS. Thereafter, the corpus luteum increases production
of both estradiol and progesterone for the next 10–12
days of the luteal phase.
Rapid vascularization of the corpus luteum appears
to be guided by angiogenic factors from the follicular
fluid.18 Continued pulsatile release of LH is critical to
the maintenance of corpus luteal function throughout
its natural lifetime.24 Wide fluctuations in circulating
progesterone result as the corpus luteum secretes
pulses of the steroid into the blood stream.25 In the
absence of human chorionic gonadotropin (hCG) stimulation of the corpus luteum, steroidogenesis in the
corpus luteum declines after 10–12 days. Circulating
progesterone concentrations swing markedly during the
luteal phase, with elevations following every LH pulse.15

Both the frequency and amplitude of GnRH pulses
change throughout the menstrual cycle in response to
feedback effects of the gonadal steroids estrogen and
progesterone on hypothalamic neuroregulators such as
dopamine and endogenous opioid peptides.
The hypothalamic GnRH pulse generator produces
one pulse per hour in the absence of ovarian restraint.12
During the luteal–follicular transition when estradiol,
progesterone, and inhibin levels fall, pulses of GnRH
occur every 90–120 minutes. In the mid to late follicular
phase, GnRH frequency increases to one pulse per hour,
favoring LH secretion, while FSH is inhibited by rising
levels of estradiol and inhibin B from the dominant follicle. Differential regulation of FSH and LH secretion
late in the follicular phase is accomplished by at least
two different mechanisms.13 First, estradiol and inhibin
A feedback to the pituitary gonadotrope to augment
LH and inhibit FSH secretion.14 Secondly, a changing
(more rapid) pattern of GnRH pulses favors LH release.15
The LH surge onsets most often between midnight and
8 am and is unlikely to occur before the follicle diameter has achieved 15 mm and or serum estradiol reaches
600 pmol/L.16
The LH surge induces resumption of meiosis, luteinization of the granulosa cells that line the interior of the
dominant follicle, and a series of inflammatory events
that precipitate follicular rupture.17 The LH surge lasts
for approximately 48 hours and ovulation occurs about
36 hours after the onset and 12 hours from the peak

In its phase of peak steroidogenic activity, the corpus
luteum appears as a swollen vascular area on the
surface of the ovary. When surgically incised, the center
appears yellowish orange due to the high concentration
of cholesterol, which forms the substrate for steroidogenesis.
In conception cycles, the embryo migrates at the
morula stage into the endometrial cavity about 4 days
after ovulation. The following day, the embryo sheds
its zona pellucida and develops a loose adherence to the
endometrium. Implantation in the human can only
occur during a 6–10 day ‘window of implantation’ and
if this happens the hCG from the early pregnancy with
its biological similarity to LH can maintain the activity
of the corpus luteum until approximately 7–8 weeks
from the last menstrual period when placental steroidogenesis takes over.26,27 (Figure 8.325).
When pregnancy does not ensue, a new cohort of follicles is recruited and the former corpus luteum involutes
slowly over several months. Grossly, the old corpus
luteum has the appearance of an inactive whitish area
of scar tissue known as the corpus albicans.

Data on total and free testosterone levels throughout
the normal menstrual cycle are limited due to challenges with conducting assays at the low levels normally found in women.28 In a recent study using very
sensitive detection methods, androgen levels were monitored on a daily basis throughout a complete menstrual
cycle in 34 healthy women between the ages of 25 and
40 years old (Figure 8.4). Serum testosterone levels
increased gradually, from 1.04 ⫾ 0.76 nmol/L in the
menstrual phase to 1.52 ⫾ 1.03 nmol/L at 3 days
before the LH surge. Total testosterone levels fell slightly
to 1.1 nmol/L in the midluteal phase. Free testosterone
levels mirrored those of total testosterone in the follicular phase, but were maintained without the modest
midluteal decline seen with total testosterone. Mean
testosterone levels during the follicular and luteal
phases were not significantly different (1.21 ⫾ 1.21 vs
1.18 ⫾ 1.21).29
Serial measurements of testosterone and free testosterone across the menstrual cycle between women with
prospectively defined PMS and controls revealed no
significant differences.30

TESTOSTERONE LEVELS

ENDOMETRIAL CHANGES DURING THE
MENSTRUAL CYCLE

The physiological roles of androgens in women remain
poorly understood. About 50% of testosterone and
androstenedione come from the ovary, with the
remainder originating in the adrenal gland.

Under the influence of rising levels of estradiol, the
endometrium shows extensive glandular mitotic activity as stromal and glandular tissues proliferate in the

follicular phase. In the luteal phase, the predominance
of progesterone results in decidualization of the
endometrium – the increase in vascularity and secretory
vacuoles that would be integral to implantation and early
embryonic development. Cytosolic vacuoles containing
prostaglandins rupture and release their contents when
progesterone levels fall late in the luteal phase. These
prostaglandins, in turn, cause blood vessels within the
endometrium to constrict, resulting in ischemic necrosis
and sloughing of the superficial endometrium. The
basal layer of endometrium is preserved and the deeper
glands constitute the source for new endometrial cells
that resurface the denuded endometrial cavity. Bleeding
typically subsides as small vessels that supply the
endometrium constrict and develop a platelet and fibrin
plug. Aberrations of coagulation (either congenital, like
von Willebrand’s disease, or acquired, such as idiopathic thrombocytopenic purpura) or fibrinolysis can
result in exaggerated flow in some women. More commonly, women with pathological abnormalities of the
endometrium (endometrial polyps) or myometrium
(leiomyomata) will report unusually heavy menstrual
flow. In the normal situation the endometrium is rapidly
resurfaced in the 5–6 days after menstruation abates.
Synchronous time-limited shedding of the endometrium results when progesterone levels decline in ovulatory women and asynchronous (incomplete) sloughing
of endometrium may result from temporary declines in
estrogen that occur in ovulatory cycles coincident with
ovulation22 but more commonly at unpredictable times
in anovulatory women. Accordingly, the pattern of
menstruation will usually confirm whether or not a
woman is ovulatory. Regular predictable cycles with an
intermenstrual interval of 24–35 days are the hallmark
of ovulatory menstrual cycles, whereas unpredictable
bleeding at intervals of weeks to months that lasts for
different durations (sometimes several weeks) is highly
predictive of anovulatory or oligo-anovulatory cycles.

INTRODUCTION
The concept that severe premenstrual affective, behavioral, and physical symptoms could be triggered by
ovulation and the rise and fall of ovarian sex steroids in
the luteal phase of the menstrual cycle was an advance
over previous notions that the symptoms resulted from
‘agitated menstrual blood seeking escape from the womb’.
Still, the explicit psychoneuroendocrine etiology of premenstrual syndrome (PMS) remains unknown, and
more than two decades of research have demonstrated
that a simple alteration of hormones, neuropeptides, or
neurotransmitters cannot completely explain the occurrence of the symptoms. The purpose of this chapter is
to provide an overview of the three leading hypotheses
that currently attempt to explain the biological basis of
PMS. To this end, we will discuss the monoamine neurotransmitter serotonin (5-hydroxytryptamine, 5-HT);
the GABAergic neurotransmitter system, in particular, the
GABAA receptor complex; and the pro-opiomelanocortin
(POMC) pathway, in particular, the endogenous opiate
peptide, ␤-endorphin.

Progesterone deficiency was also excluded by studies
demonstrating that progesterone concentrations are
not lower in women with PMS compared with controls.2–4 Furthermore, PMS symptoms were found to be
more severe in cycles with higher concentrations of
both estradiol and progesterone.5 Finally, a series of
double-blind placebo-controlled treatment trials failed
to demonstrate progesterone supplementation to be
more efficacious than placebo.6–8
Since ovulation and probably progesterone production trigger the symptoms of PMS, investigations
proceeded into the neuroactive metabolites of progesterone and their role in the genesis of PMS symptoms.
Progesterone is metabolized in the ovary and the brain
to form the potent neuroactive steroids, 3␣-hydroxy5␣-pregnan-20-one (allopregnanolone) and 3␣-hydroxy5␤-pregnan-20-one (pregnanolone), positive allosteric
modulators of the ␥-aminobutyric acid (GABA) neurotransmitter system in the brain. The contribution of
this receptor system to the genesis of the premenstrual
symptoms is also discussed in further detail in
Chapter 13.

GABA physiology
GABA NEUROTRANSMITTER SYSTEM
Clinical background
The symptoms of PMS are more severe in the 5–7 days
before menses, as progesterone levels decline in the late
luteal phase of the menstrual cycle. The first neuroendocrine hypothesis therefore logically stated that progesterone deficiency or withdrawal could elicit the
symptoms of PMS. However, the mood deterioration
generally begins in parallel with the rise in the production of progesterone by the corpus luteum, suggesting
hormone withdrawal cannot explain the symptoms.1

GABA, the main inhibitory neurotransmitter in the
mammalian brain, is the most widely distributed amino
acid neurotransmitter in the central nervous system
(CNS), crucial for the regulation of anxiety, vigilance,
alertness, stress, and seizures.9 Most neurons are sensitive to GABA. GABA is derived from glucose metabolism: ␣-ketoglutarate formed by the Krebs (tricarboxylic
acid) cycle is transaminated by GABA-oxoglutarate
transaminase (GABA-T) to the amino acid, glutamate.10
Found exclusively in GABAergic neurons, glutamic acid
decarboxylase (GAD) catalyzes the rate-limiting decarboxylation of glutamate to GABA.11 GABA is then

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stored in vesicles concentrated in the presynaptic terminal until it is released by a nerve impulse.
GABA postsynaptic receptors are classified into three
subtypes: GABAA, GABAB, and GABAC receptors.12 The
type A (GABAA) receptor is a basic control mechanism
fundamental to the functioning of the CNS, and is the site
of action for endogenous neuroactive hormonal steroids
as well as exogenous agents such as benzodiazepines,
barbiturates, alcohol, and anticonvulsants that regulate
mood and behavior.9,13 The GABAA receptors are plasma
membrane-bound protein complexes that form an ionpermeable channel. Specifically, GABAA receptor activation by GABA results in rapid and transient responses
entailing the opening of a chloride anion channel leading
to neuronal chloride influx, decreasing the likelihood
of depolarization by excitatory neurotransmitters. This
hyperpolarization is inhibitory since it represents a
move away from the action potential threshold.
The GABAA receptor is distributed ubiquitously
throughout the brain. Benzodiazepines, barbiturates,
steroid hormones, and ethanol are all positive allosteric
modulators or agonists of this receptor. Binding of such
a modulator shifts the GABA response curve to the left,
enhances the effect of synaptically released GABA, and
potentiates the GABA response. Inhibitory compounds
such as the ␤-carbolines shift the GABA concentration
response curve to the right and are termed negative
modulators or inverse agonists.9,14,15 Antagonists such
as bicuculline bind to the GABA binding site but do not
open the chloride channel. The 3␣-hydroxy-5␣-pregnan20-one (allopreganolone), corticosterone, and testosterone
metabolites, barbiturates, benzodiazepines, and probably ethanol all have separate extracellularly directed
binding sites on the GABAA receptor, which can increase
neuronal inhibition. Some steroids, such as pregnenolone sulfate and dehydroepiandrosterone (DHEA)
can act as negative modulators; penicillin, picrotoxin,
calcium, and bicuculline also decrease the GABA
response and inhibit GABAA receptor chloride channel
flux9 (Figure 9.1).
Classically, activation of steroid hormone receptors
results in transcription and translation of specific
genes. However, in contrast to the slower (hours to
days) genomic effects of most cytosolic steroid hormone
receptors, GABA release through neurosteroid modulation of the GABAA membrane receptor is direct and
rapid (within minutes). Synaptic GABA transmitter
inactivation is primarily through reuptake. In addition,
both glia and neurons possess these proteins and reuptake GABA. Once GABA is taken up, it can be enzymatically inactivated.16
GABAA, but not GABAC and GABAB, receptors have
been associated with alterations in mood, cognition,
and affect. Ovarian and adrenal steroids are potent

Picrotoxin
site
Barbiturate
site

GABA site

α

Steroid
site
Benzodiazepine
site

β

γ

α
β

Figure 9.1 Theoretical model of the GABAA receptor
complex and its various ligand binding sites.
(Reprinted from N-Wihlbäck et al,37 with kind
permission from Springer Science and Business
Media.)
modulators of the GABAergic system in the brain.
Increasing plasma concentrations of progesterone and
corticosterone give rise to higher brain concentrations
of neurosteroids, which suggests that plasma progesterone and corticosterone are significant sources of substrate for neurosteroid formation.17 Neurosteroidogenesis
begins with the conversion of cholesterol to pregnenolone by the cytochrome P450 side chain cleavage
enzyme located in the inner mitochondrial membrane
of glial cells18 (Figure 9.2). In the brain, pregnenolone
can be converted by the 3␤-hydroxysteroid dehydrogenase isomerase (3␤-HSD) into progesterone, which is
also a neuroactive steroid because in nanomolar concentrations it can bind to intracellular (nuclear) progesterone receptors and control the transcription of specific
genes in neurons or glial cells.18 The main pathway
of progesterone metabolism in the brain and the
ovary is its conversion into 5␣-dihydroprogesterone
catalyzed by type I 5␣-reductase and the conversion of
5␣-dihydroprogesterone into 3␣,5␣-TH PROG (allopregnanolone) catalyzed by the 3␣-hydroxysteroid
oxide reductase (3␣-HSD). Endogenously produced
3␣,5␣-TH PROG plays an important physiological
modulatory role in tuning the sensitivity of GABAA
receptors to GABA or to other agents (e.g. benzodiazepines) that act by binding to GABAA receptors.17,19,20
The GABAA receptor is most commonly composed
of ␣, ␤, ␦ and/or ␥-subunits, the specific composition of
which confers flexibility and partially explains the
specificity for neurosteroid activity20,21 (see Figure 9.1).
The ␣2 subunit of the GABAA receptor is mainly

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NEUROTRANSMITTER PHYSIOLOGY 71
O

O

O

O

HO

H
5α-DHP

H
Allopregnanolone
O

Figure 9.2 Synthesis of
progesterone metabolites.
(Reprinted from
N-Wihlbäck et al,37 with kind
permission from Springer Science
and Business Media.)

O

O
Progesterone
O

H

HO

5β-DHP

expressed in brain regions associated with emotional
stimulus, such as the hippocampus and amygdala.22
Receptors containing the ␦ subunit in combination
with the ␣4 subunit, are highly sensitive to the ovarian-,
adrenal-, and brain-derived neurosteroid allopregnanolone and to the adrenal- and brain-derived
neurosteroid
3␣,5␣-tetrahydrodeoxycorticosterone
(3␣,5␣-THDOC).20
Acute stress, pregnancy, or progesterone exposure in
a rodent model simulating the luteal phase of the menstrual cycle all result in increased neurosteroid production, which confers short-term changes in GABAA
receptor composition, e.g. up-regulation of ␣4, ␦, and ␥
subunit expression. This GABAA plasticity results in
temporarily decreased sensitivity to GABA and GABA
agonists. For example, after withdrawal of allopregnanolone, there is a marked decrease in GABAA-gated
chloride influx in hippocampal neurons and increased
neuronal excitability.23–28 Progesterone therefore indirectly, through its metabolite allopregnanolone, increases
the expression of the ␣4, ␥2, and ␦ subunits of the GABAA
receptor.
The ␣4 subunit of the GABAA receptor has been
linked to anxiety.29 Increased ␣4 subunit is observed in
the rat model in the postpartum state and after withdrawal from progesterone, and has been associated
with anxiety-like reaction in the maze plus and prod
burial tests.23,29–31 Expression of the ␥2 subunit is also
altered by pregnancy and postpartum states, estrous
and menstrual cycle fluctuations in progesterone, and
even administration of oral contraceptives.31–33 During
the rodent ovarian cycle, elevated expression of the ␦
subunit of the GABAA receptor results in decreased
seizure susceptibility and lowered anxiety levels.28
Thus, exposure to the progesterone metabolite allopregnanolone alters the subunit composition of the GABAA

H
Pregnanolone

receptor, rendering the receptor temporarily insensitive
to modulation by neurosteroids.24,26,34–36

GABAA receptor, neurosteroids,
and mood symptoms
These alterations of GABAA receptor isoforms, which
result in reduced neurosteroid sensitivity, are very likely
to be important in the etiology of PMS, postpartum
mood disorders, and even the adverse psychological
effects of progesterone and progestins.37 CNS concentration of these neuroactive metabolites, duration of
exposure, as well as genetic predisposition are important determinants of GABAA receptor agonist effect.
Acute treatment with allopregnanolone has been
shown to have anxiolytic, antidepressive, and anticonvulsant effects38,39 and decreased neuroactive steroids
have been associated with anxious and depressive
behavior.40,41 That allopregnanolone may play a role in
affecting mood is apparent from the fact that improvement of unipolar depression by fluoxetine treatment
lasting 8–10 weeks was correlated with a normalization of endogenous CSF allopregnanolone content,
which was significantly decreased prior to fluoxetine
treatment.41 Decreased GABA synthesis and activity in
the brain have also been associated with depression
and mood disorders.42 Helpless, chronically stressed and
anxious rodents have significantly decreased GABAA
receptor expression, GABAA receptor-medicated chloride ion flux, and decreased sensitivity to GABAA receptor
modulators.43–46
Similarly, human patients with mood disorders and
PMS have been shown to be insensitive to modulatory effects of benzodiazepines and have altered
GABAA receptor expression and function.37,47,48 Studies
of plasma neuroactive steroids in PMS have been

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72 THE PREMENSTRUAL SYNDROMES

contradictory with some49,50 but not others,51–53 suggesting a deficiency of allopregnanolone. However,
analogous to the rodent model of progesterone exposure, decreased sensitivity to GABAA agonists, including
neuroactive steroids, has been demonstrated in the
luteal phase in women with PMS.54,55 Women with
PMS demonstrate decreased pregnanolone responsiveness possibly due to altered sensitivity of GABAA receptors54 and there is some evidence to suggest that
patients with mood disorders are also insensitive to
modulatory effects of benzodiazepines.47,48
The length of allopregnanolone exposure thus plays
a critical role in the regulation and function of the
GABAA receptor. Whereas acute, short-term allopregnanolone exposure decreases anxiety, chronic exposure
to elevated allopregnanolone can produce decreased
expression and binding to the GABAA receptor as well
as uncoupling of the receptor from several anxiolytic modulators, leading to increased anxiety.56,57 Progesterone
metabolite effects on mood and behavior also appear to
be biphasic in nature.37 In high concentrations, pregnanolone and allopregnanolone produce anxiolytic,
sedative, antiepileptic, and anesthetic effects.58–60 At
lower physiological levels, though, allopregnanolone
can cause anxiety, aggression, impulsive behavior, and
negative mood in predisposed individuals.29,61,62 In
sum, GABAA receptor function and modulation probably varies throughout the menstrual cycle and probably
contributes to the negative mood symptoms experienced by many women during the luteal phase.

SEROTONIN NEUROTRANSMITTER SYSTEM
Clinical background
Depression is one of the most serious symptoms of
PMS. The monoamine theory of depression posits deficiency of norepinephrine and also the indole amine,
serotonin (5-HT). Serotonergic dysfunction has been
implicated in the etiology of PMS, and currently, one of
the treatments of first choice for severe PMS/PMDD
(premenstrual dysphoric disorder) is a serotonergic antidepressant. However, the absence of biological markers
for depression in women with PMS (e.g. failure of dexamethasone to suppress cortisol),63,64 reduced platelet
monoamine oxidase (MAO) B,65 and the rapid response
to serotonergic antidepressants suggest that PMS is not
a subset of depressive or anxiety disorders and that the
neurophysiology is likely to differ. The serotonin
hypothesis is also hampered by incomplete understanding of the neurophysiology of the serotonergic system,
as well as the lack of a complete response to serotonergic medications by all women with PMS.

Serotonin physiology
Serotonin (5-HT, 5-hydroxytryptamine) is synthesized
within serotonergic neurons and in several types of
peripheral cells.66 The brain accounts for about 1% of
the total body stores of 5-HT. The amino acid tryptophan is transported to the CNS via an active transport
pump.67 Two enzymes sequentially alter tryptophan:
tryptophan hydroxylase is the rate-limiting step in the
formation of 5-HT, producing 5-hydroxytryptophan
(5-HTP); then the L-aromatic amino acid decarboxylase decarboxylates the hydroxylated tryptophan,
resulting in serotonin (5-HT).68,69
5-HT cannot cross the blood–brain barrier; thus,
CNS neurons must synthesize the amine. Tryptophan
is present in high levels in plasma, and changes in
dietary tryptophan can substantially alter brain levels
of 5-HT.70 The availability of dietary tryptophan is
important in regulating 5-HT synthesis.71 Since other
large neutral aromatic amino acids compete for transport into the CNS, brain levels of tryptophan are also
dependent upon plasma concentrations of other competing neutral amino acids.67 5-HT is then stored in
vesicles concentrated in the presynaptic terminal until it
is released by a nerve impulse (Figure 9.3).
Impulse-modulating and release-modulating receptors, designated 5-HT1A somatodendritic autoreceptor
and 5-HT1D terminal autoreceptor, are located on the
cell body and the nerve terminal, respectively, and
detect the presence of 5-HT and then regulate the
release and firing rate of 5-HT neurons.66,72 Drugs that
block the 5HT1D autoreceptor increase 5-HT release
and are under development. The serotonergic neuron
also has a terminal autoreceptor, the ␣2 heteroreceptor,
that, when occupied by norepinephrine, turns off serotonin release (Figure 9.4), as well as an ␣1 heteroreceptor on the cell body that can enhance serotonin
release.73 5-HT that is released into the synapse is inactivated primarily by reuptake through the high-affinity
presynaptic membrane serotonin transporter (SERT) or
‘reuptake pumps’. SERT is an important clinical target
for therapeutic drugs, such as selective serotonin reuptake inhibitors (SSRIs).74 The enzymatic degradation of
5-HT is catalyzed by the MAO enzyme located within
the serotonergic neuron, producing 5-hydroxyindoleacetic acid (5-HIAA). Low cerebrospinal fluid
(CSF) 5-HIAA has been found in patients with antisocial, borderline, self-destructive personality disorders
and poor impulse control and those who are prone to
aggressive outbursts and violent suicide.73,75,76
However, as noted above, the MAO inhibitors and
tricyclic antidepressants, both of which increase all
three monoamine neurotransmitters, but particularly
norepinephrine, and which were effective for the

treatment of depression, were not useful for the treatment of PMS. These agents are not selective for serotonin. Also, SSRIs increase serotonin acutely,
particularly in the region of the 5-HT1A autoreceptor,
but there is a 3–8 week delay for the antidepressant
effect of the serotonin-augmenting drugs when used for
the treatment of depression, but not however for PMS
and PMDD.77,78 The delayed treatment response in
affective disorder has been explained by the neurotransmitter receptor theory, suggesting that monoamine
depletion results in 5HT receptor up-regulation and
symptoms of depression. Prolonged drug exposure
would then be necessary to desensitize the 5-HT1A
autoreceptors and to down-regulate postsynaptic

receptors. A neurophysiological explanation for the
rapid response to SSRIs in PMDD remains unknown.
5-HT postsynaptic receptors are classified into four
subtypes, 5-HT1 to 5-HT4, with further subdivision of
the 5-HT1 subtypes:79 the most important for mood regulation include the 5-HT1A, 5-HT2A, and 5-HT2C.80–82
The 5-HT3 receptor is especially important as a chemoreceptor that controls emesis, and 5-HT3 and 5-HT4
receptors help to regulate gastrointestinal motility and
appetite.83,84 Side effects of serotonergic drugs such as
SSRIs are generally related to the stimulation of the
5-HT 2A, 2C, 3, and 4 receptor subtypes. Acute stimulation of 2A and 2C receptors in various brain and
peripheral regions can lead to agitation, restlessness,

myoclonus, nocturnal awakenings, and sexual dysfunction.73 5-HT3 and 5-HT4 receptors may be responsible
for the gastrointestinal side effects of nausea, cramps,
and diarrhea.83
Cell bodies containing serotonin are found primarily
in the raphe nucleus of the brainstem and in nerve
endings diffusely distributed throughout the brain.66
5-HT has been implicated in modulation of circadian
rhythms, eating, mood, sleep, and arousal.85 Projections
from the raphe nucleus to the frontal cortex are
important in mood regulation.86 Projections to the basal
ganglia help control movements and obsessions and compulsions.87 Those to the limbic area are implicated in
anxiety and panic reactions, whereas those to the hypothalamus regulate appetite and eating disorders.88,89
Serotonergic neurons in the brainstem regulate sleep.90
Projections down the spinal cord are involved in spinal

reflexes for sexual responses of orgasm and ejaculation.91
5-HT also has hormone-like effects when released into
the bloodstream, regulating smooth muscle contraction
and affecting platelet aggregation and immune systems.
A deficiency of the serotonergic system could cause
depression, anxiety, panic, obsessions, compulsions,
and cravings for food.86–89
Serotonergic activity in the brain is also affected by
estrogen and progesterone. Sex steroids can modify serotonin availability at the neuronal synapse.92 Estrogen
augments serotonin by increasing degradation of MAO
and catechol O-methyltransferase (COMT), regulating
the availability of free tryptophan in the brain, enhancing serotonin transport, and increasing the density of
5-HT-binding sites in brain regions affecting mood and
cognition.93 This is important, since MAO and COMT
degrade 5-HT and determine its synaptic availability.

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NEUROTRANSMITTER PHYSIOLOGY 75

Estrogen has also been shown to improve the clinical
effect of SSRIs.94
By contrast, progesterone increases MAO and COMT
enzyme activity, acts as an antiestrogen, and downregulates estrogen receptors.93 Exogenously administered synthetic and natural progestins can induce negative
mood, but this effect is dependent upon relative estrogen
and progesterone dosages.93,95,96 In summary, progesterone increases MAO, which decreases 5-HT availability and depressed mood, whereas estrogen decreases
MAO activity, thus increasing 5-HT availability with
resulting antidepressant effect.97 It may be that these
inter-relationships of sex steroids and serotonergic function are an oversimplification of the true picture and
there may be some contradictions that will become
evident as more research becomes available.

the activity of 5-HT neurons in the dorsal raphe nucleus
through allopregnanolone-potentiated GABAA-mediated
inhibition.108 Additionally, serotonergic neurons often
terminate at inhibitory GABAergic interneurons in
the hippocampus, suggesting a direct interaction.109
5-HT1a and 5-HT3 receptors have been localized to
GABA interneurons in the cortex and hippocampus.110,111
In the piriform cortex, 5-HT1a has been shown to increase
the firing rate of GABAergic neurons.112 Futhermore,
in-vivo administration of a 5-HT1A receptor agonist
enhances GABAA-stimulated chloride ion influx.113 In
5-HT1A receptor knock-out mice, there is an alteration
of GABAA receptor subunits, receptor binding is
reduced, and the mice develop benzodiazepine-resistant
anxiety.114 There clearly is a complex interaction between
GABA and 5-HT neurons that may partially explain
their influence on premenstrual mood and behavior.

Serotonin, affective symptoms and PMS
Clinical substantiation for the role of serotonin in premenstrual disorders is supported by various lines of evidence, including:

ENDOGENOUS OPIOID PEPTIDES

1.

The endorphin hypothesis of PMS was based on the
recognition that some of the symptoms of PMS resembled those of opiate addiction and withdrawal, i.e. fatigue,
depression, tension, anxiety, irritability, headaches, and
pain sensitivity. It was hypothesized that women could
become addicted to their own endogenous opiate peptides (EOPs).115 One study demonstrated prevention of
PMS symptoms with full-cycle treatment with naltrexone, an opioid antagonist used for opiate addiction.116

2.

3.

4.

Similarity between symptoms of PMS and those
triggered by serotonin depletion paradigms,4,98,99
such as depression and impulsive/aggressive behavior, irritability, anxiety, food cravings, and weight
gain.
Decreased luteal phase platelet uptake of serotonin,100 decreased luteal phase whole blood 5-HT
at baseline,101 and after either oral102 or intravenous L-tryptophan challenge.103
Lack of significant improvement of PMS symptoms with antidepressants that augment only norepinepherine but not serotonin.
Numerous double-blind placebo-controlled trials
demonstrating the efficacy of serotonergic agents
administered continuously or solely in the luteal
phase for the treatment of the severe form of PMS,
premenstrual dysphoric disorder (PMDD).104,105

It must be remembered that extrapolation of therapeutic response to causality must always be viewed with
caution.

SEROTONIN, GABA, AND PMS
There is evidence to support a link between the
GABAergic and serotonergic neurotransmitter systems,
and this link may be relevant to depressive disorders
and PMS. SSRI treatment for major depression
increases GABA concentration, especially in the occipital cortex.106,107 GABA has been shown to regulate

Clinical background

Endogenous opioid peptide physiology
Endogenous opioids include endorphins, enkephalins,
dynorphins, and other peptides. Pro-opiomelanocortin
(POMC) is the 31-kDa glycopeptide precursor that is
cleaved to a number of smaller peptides, including
endorphins, enkephalin, adrenocorticotropic hormone
(ACTH), and melanocyte-stimulating hormone (MSH).117
Proteolytic processing of POMC to certain small fractions appears to be tissue-specific, depending on the
region of the brain.118 POMC has been demonstrated
in the anterior and intermediate lobes of the pituitary
gland, hypothalamus, brain, sympathetic nervous system,
lungs, adrenal medulla, gastrointestinal tract, reproductive tract, and placenta.119–121 Proenkephalin A is a precursor for enkephalins, whereas proenkephalin B is the
precursor for dynorphins. Proenkephalin A has been
found in the adrenal medulla, posterior pituitary
gland, brain, spinal cord, and gastrointestinal tract.121
Proenkaphalin B is found in the brain and gastrointestinal tract.121

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76 THE PREMENSTRUAL SYNDROMES

These endogenous opioid peptides bind to a multiplicity of opioid receptors, with different opiates possessing different selectivity for particular receptors.121
Five opioid receptor types have been proposed, consisting of the ␮, ␦, ␬, ␧, and ␴ receptors.122,123 Morphine
binds preferentially to the ␮-receptor, enkephalins to
the ␦-receptor, ␤-endorphin to the ␧ receptor, and
dynorphin to the ␬ receptor.124 The distribution of morphine and enkephalin receptors in the brain has been
investigated with equal numbers in the cerebral cortex
and striatum, twice as many morphine receptors as
enkephalin receptors in the limbic system, hippocampus,
and brainstem, and four times greater morphine receptors in the thalamus and hypothalamus.125
Specifically, ␤-endorphin is a polypeptide containing
31 amino acids with 5–10 times the potency of morphine. Endorphins regulate gonadotropin secretion and
mediate pain response. Although widely distributed in
the body, endorphins have the highest concentration
within the arcuate nucleus and median eminence of
the hypothalamus and the intermediate lobe of the
pituitary gland.126,127 The medial basal hypothalamus,
which incorporates the arcuate nucleus, is an area also
highly concentrated in gonodotropin-releasing hormone
(GnRH)- and dopamine-containing cells.128 High concentrations of ␤-endorphin have been found in the
hypophyseal portal blood, suggesting that endogenous
opioids of hypothalamic origin are secreted into the
portal blood and may directly regulate pituitary peptide
hormone secretion.129 However, most studies support
the notion that endogenous opioids probably decrease
pituitary gonadotropin secretion by exerting effects on
hypothalamic GnRH secretion, where endorphins are
located in close proximity to GnRH-secreting cells,
rather than direct pituitary stimulation.130–132
The concentration of ␤-endorphin in the hypophyseal portal blood varies in relation to the menstrual
cycle. Studies in female monkeys have shown that ␤endorphin is present in high concentrations during the
mid-to-late follicular phase and the luteal phase, but
undetectable at the time of menses and after ovariectomy.133 Chronic administration of estrogen or estrogen
with progesterone in ovariectomized monkeys restored
detectable levels of ␤-endorphin in the hypophyseal
portal blood.134 These results suggest that ovarian
steroids effect the release of hypothalamic ␤-endorphin
into the hypophyseal portal blood, and cyclic changes
in sex steroids during the menstrual cycle may affect
anterior pituitary gonadotropin secretion through a
mechanism involving ␤-endorphins.
In normal human subjects, opiate administration
results in a significant decrease in luteinizing hormone
(LH) secretion and an increase in prolactin secretion.135
Naloxone, a competitive opioid antagonist, blocks the

different subtypes of opioid receptors with different
affinities, and has the greatest affinity for the ␮ and ␧
receptors. Naloxone administered in the late follicular
and mid-luteal phases of the menstrual cycle in women
increases the frequency and amplitude of LH pulses
and circulating LH concentration, which suggests that
endogenous opiates are involved in the regulation of
LH secretion during the high estrogen and estrogen–
progesterone phases of the menstrual cycle.136,137
However, naloxone has no discernible effect on LH release
during the early follicular phase when ovarian steroid
secretion is minimal, further suggesting that gonadal
steroids modify endogenous opiate activity.136,138 The
mid-cycle rise of estrogen and progesterone probably
induces central opioid activity. Endogenous opioid
activity is low in oophorectomized women, but estrogen treatment increases opioid activity and the addition of a progestin further increases the opioid activity.
For example, in oophorectomized women treated with
chronic conjugated estrogens or conjugated estrogens
with medroxyprogesterone acetate, serum LH increases
during naloxone infusion to levels found in ovulatory
women.139 In summary, evidence suggests that ␤endorphin is an important determinant in modulating
gonadotropin secretion during the menstrual cycle.

Endogenous opioid peptides, affective
symptoms, and PMS
Differences in ␤-endorphin levels during the menstrual
cycle have been established comparing women with
PMS to controls. The ␤-endorphin levels are significantly lower during the luteal phase in women experiencing PMS.140,141 Additionally, in control women,
central opioid tone is enhanced during the mid luteal
phase and becomes minimal in the late luteal phase, but
women with PMS have low central opioid activity
during the mid and late luteal phase as indicated by the
loss of naloxone-induced LH release.142–144 Low opioid
tone has been associated with dysphoria, retarded
motor activity, emotional liability, and lethargy, symptoms that are similar to those of PMS.145,146 Therefore,
attenuated central opioid tone may play a role in the
pathophysiology of PMS.
There has also been evidence to suggest that endogenous opioid peptides may inhibit LH secretion through
influence on the hypothalamic serotonergic system.
Specifically, endogenous opiates seem to induce the
release of serotonin and increase its turnover.147–151 A
dysfunction in this opioid–serotonin relationship could
also contribute to the development of PMS symptoms,
with decreased central opioid activity leading to lowered
serotonin levels and mood deterioration.

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NEUROTRANSMITTER PHYSIOLOGY 77

In conclusion, it appears that the genesis of the symptoms of PMS may entail alterations of the serotogenic,
GABA, and the endorphin systems. There is a growing
body of evidence for the interaction of these networks
in production of severe premenstrual symptoms. SSRIs,
the current treatment of choice for PMDD, increase the
activity of the enzymes required for the formation of
allopregnanolone and, as a result, brain and CSF allopregnanolone concentrations.41,152,153 Another serotonergic compound, L-tryptophan was also shown to
increase peripheral allopregnanolone in women with
PMS.154 Reduced luteal phase GABAergic sensitivity in
women with PMS was normalized after the administration of an SSRI.54
The connection between the GABAA receptor system,
serotonin, and EOPs was recently highlighted by an
investigation of LH response to an estrogen challenge,
suggesting increased GnRH activity in women with
PMS.155 After estrogen exposure, GnRH is restrained
tonically by GABA and by endogenous opioid peptides41 and serotonin modulates the GABAA receptor
complex.155,156 Clearly, the fluctuation of sex steroids
across the menstrual cycle profoundly affects all three
candidate systems and it is likely that genetically programmed and environmentally driven differences are
responsible for the defining features of each individual’s affective, behavioral, and physical premenstrual
state.

INTRODUCTION
A comprehensive review of the early endocrine studies
of premenstrual syndrome (PMS) was performed by
Reid and Yen1 and, as described elsewhere,2 most of
these studies suffered from methodologic flaws, including the use of inadequate diagnostic criteria. PMS is a
time-oriented not a symptom-oriented diagnosis and
requires prospective demonstration that symptom appearance is confined primarily to the luteal phase of the
woman’s menstrual cycle. Since 1983, the use of two
sets of diagnostic guidelines – Diagnostic and Statistical
Manual of Mental Disorders, fourth edition (DSMIV),3 and National Institute of Mental Health (NIMH)
Premenstrual Syndrome Workshop Guidelines, unpublished work4 – has permitted greater homogeneity of
samples across studies, a requirement for comparison,
and generalization of results obtained. Data subsequently
generated provide little if any evidence for a role of
hormone excess or deficiency in the etiology of PMS.
Hormonal studies in women with PMS have employed
several different strategies:
●

●

●

●

examination of symptoms after the administration
of hormones hypothesized to be deficient in women
with PMS
measurement of basal hormone levels at selected
points in the menstrual cycle
evaluation of dynamic endocrine function employing frequent serial monitoring of hormone secretion
or endocrine challenge paradigms
manipulation of menstrual cycle physiology in order
to examine the plasticity of the linkage between the
menstrual cycle and PMS symptoms.

The most frequently employed strategy has been the
comparison of luteal phase basal hormone levels with
those from the follicular phase in women with PMS or
with comparable values from a non-PMS control group.

In this chapter we focus on the roles of ovarian
steroids in the pathophysiology of PMS. Additionally, we
include studies investigating hypothalamic–pituitary–
adrenal (HPA) axis function in PMS, since this axis is
regulated by ovarian steroids, and abnormalities of HPA
axis function are reported in PMS. First, we provide
background information reviewing the physiology of
ovarian steroids and their cellular mechanisms of action.
Secondly, we describe examples of the neuromodulatory
actions of gonadal steroids in both preclinical and human
studies. Thirdly, we focus on the regulatory effects of
gonadal steroids on systems relevant to the pathophysiology of PMS and affective adaptation, including a
section on the regulatory effects of ovarian steroids on
HPA axis function. Finally, we present studies on the
role of ovarian hormones in PMS categorized on the
basis of the research strategies employed.

GONADAL STEROID HORMONES
Synthesis and metabolism
Gonadal steroids, like all steroid hormones, are derivatives of cholesterol. Steroidogenic acute regulatory
protein (STAR) is the critical regulator of cholesterol’s
availability within the mitochondria, where it is converted by the enzyme cholesterol desmolase to pregnenolone.5,6 Pregnenolone then serves as the precursor
for the whole family of steroid hormones, individual
members of which are generated through the actions of
a relatively small number of enzymes with multiple
sites of action (Figure 10.1). The resulting end products
of this cascade are determined by the tissue in which
the metabolism is occurring and the enzymes present in
that tissue. For example, testosterone may be the end
product and act directly at the androgen receptor, or it
may be reduced to a form with greater affinity for the
androgen receptor (dihydrotestosterone), converted to

a form with less affinity for the androgen receptor
(androsterone), or aromatized to estradiol and act through
the estrogen receptor.
As steroid hormones are highly homologous and serve
as precursors for one another, the manner in which
steroids are metabolized can markedly change the amplitude or nature of the steroid signal. Steroid metabolic
enzymes, then, can contribute to the variance in a steroid
signal in several ways. First, enzymes regulate the activation and potency of steroid hormones: seen, for example,
with the enzyme (5␣-reductase), which converts testosterone into dihydrotestosterone (DHT), an androgen with

fourfold greater affinity for the androgen receptor and
fivefold greater stability.7 Secondly, enzymes determine
the receptor system that is activated: seen, for example,
in the conversion by aromatase of testosterone (acting
at the androgen receptor) to estradiol (acting at estrogen
receptors ␣ and/or ␤). Thirdly, the metabolism of steroids
can facilitate or inhibit the accumulation of metabolites
that may be neurotoxic: seen, for example, with the
ability of 5␣-reductase to shunt testosterone away from
the pathway, leading to accumulation of estradiol, which
can function as a neurotoxin.8,9 Fourthly, enzymes may
produce steroid metabolites that have a completely

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PATHOPHYSIOLOGY I: ROLE OF OVARIAN STEROIDS 85

different neuromodulatory profile from that of the parent
hormones: seen, for example, with the conversion of
progesterone to the neurosteroid allopregnanolone or
DHT to the neurosteroid androsterone (by 5␣-reductase
and 3␣-hydroxysteroid oxidoreductase [3␣-HSOR]), both
potent modulators of the ␥-aminobutyric acid (GABA)
receptor chloride ionophore.10,11 Since many of the
enzymes have multiple steroid substrates, a single
enzyme’s activity may regulate the relative amounts of
different behaviorally active metabolites: for example,
3␣-HSOR both inactivates the androgen DHT (at the
androgen receptor) and produces the neurosteroids allopregnanolone and androsterone.12 Not only will different
metabolic profiles activate or inhibit different receptor
systems but also the consequence of the activation of a
given steroid receptor will differ depending upon which
hormones are present. Estradiol and cortisol, for example,
exert opposing effects on AP1-modulated genes through
interactions with the cointegrator CBP/P300.13 A steroid
hormone, then, may produce markedly different effects,
depending upon its metabolism and the hormonal context
in which it is acting. Finally, abnormalities of these
metabolic enzymes occur secondary to genotypic variation and, therefore, one metabolic product could be
selectively favored over others. Several genetically based
abnormalities of steroid metabolism exist, and investigators speculate that similar variants in the enzymes
required for neurosteroid synthesis may underlie behavioral disorders, including PMS.

Mechanisms of actions
The classic action of steroid hormones occurs after the
steroid binds (activates) its intracellular receptor,
which, after undergoing phosphorylation and release
from heat shock proteins, binds (usually as a dimer) to
a hormone response element on a gene and directs or
modifies transcription of that gene. Once the ligand–
receptor complex binds to the hormone response
element (which is located on or near the promoter of
the gene), the result can be either the initiation or repression of transcription of messages coding for an array of
proteins, including synthetic and metabolic enzymes
for neurotransmitters, neuropeptides, receptor proteins
(both membranous and intracellular), transporters, and
second messengers.
Several factors may influence the genomic actions of
gonadal steroids and account for their widespread and
variable effects. First, isoforms of both the androgen
and progesterone receptors exist, and each isoform has
different transcriptional effects. Two separate estrogen
receptors, ␣ and ␤, exist and are coded for by genes on
the 6th and 14th chromosomes, respectively. These estrogen receptors have different distributions in the brain,

different transcriptional actions, and even possess additional isoforms (e.g. insertional and deletional variants
of ER ␣ and ␤). Secondly, the activated steroid receptor
regulates transcription by binding protein intermediaries
called coregulators (both stimulatory and inhibitory).
Coregulators are expressed in a tissue-specific fashion,
and their differential localization may contribute to functional variability in the effects of the same hormone in
different tissues despite the presence of similar concentrations of both ligand and receptor. Thirdly, activated
hormone receptors can influence the transcription of
genes that do not possess hormone response elements
through interactions with other cellular proteins called
cointegrators, which enable hormones to regulate genes
at transcription factor binding elements (e.g. AP-1, SP-1
sites). Fourthly, steroid hormone receptors can be activated by a variety of neurotransmitters (e.g. dopamine
through D1 receptor) and growth factors, even in the
absence of steroid hormones. In this fashion environmental events (e.g. stressors) can impact the response to a
steroid hormone signal. Finally, hormones may influence
each other’s activity by competing for cofactors or by
producing opposing regulatory effects on genes through
integrator proteins.
The relatively slow, ‘genomic’ effects of gonadal steroids
have been expanded in two dimensions: time, with a
variety of rapid (seconds to minutes) effects observed;
and targets, which now include ion channels and a variety
of second messenger systems. For example, estradiol (E2),
in just minutes, increases firing of neurons in the cerebral cortex and hippocampus (CA1)14 and decreases firing
in medial preoptic neurons.15 The activity of membrane
receptors like the glutamate and GABA receptors is
acutely modulated by gonadal steroids (estradiol and the
5␣-reduced metabolite of progesterone, allopregnanolone,
respectively).10,16 Estradiol binds to and modulates the
Maxi-K potassium channel,17 increases cyclic adenosine
monophosphate (cAMP) levels,18 regulates membrane G
proteins (G.αi, G. αq; G.αs)19 (Manji et al, unpublished work),
inhibits L-type calcium channels (via non-classical receptor),20 and immediately activates the mitogen-activated
protein kinase (MAPK) pathway (albeit in a receptormediated fashion).21 The effects observed are tissue- and
even cell-specific (e.g. estradiol increases MAPK in
neurons but decreases it in astrocytes).22,23 Finally, both
estradiol and progesterone24,25 phosphorylate dopamineand cAMP-regulated phosphoprotein-32 (DARPP-32),
which is an important regulator of the phosphorylation
state of many cellular proteins and, therefore, an important
regulator of neural function.26 The increase in the number
of described mechanisms by which gonadal steroids can
impact on cell function has paralleled the rapid growth in
their observed effects. Consequently, with each of these
newly identified actions (which are usually, but sometimes

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86 THE PREMENSTRUAL SYNDROMES

inaccurately, called ‘non-genomic’), one needs to examine
multiple factors prior to inferring the mechanism of action:
●
●

●

●

●
●

the duration required to see the effect
the impact on the effect of inhibitors of transcription
and protein synthesis
the presence (or absence) of intracellular steroid
hormone receptors
the stereospecificity of ligand binding (to see if
effects are mediated through a classical receptor)
the effect of hormone receptor blockers
the ability of the ligand to initiate the action from
the cell membrane (i.e. when entry into the cell is
blocked).

This last requirement acknowledges the presence on the
membrane of binding sites for gonadal steroids that
increasingly seem to be physiologically relevant.27

NEUROMODULATORY EFFECTS OF
OVARIAN STEROIDS
The best support for the importance of the neuromodulatory actions of gonadal steroids is found in their
dramatic and widely ranging effects on the brain. In
fact, gonadal steroids have been shown to play a role in
all stages of neural development, including neurogenesis, synaptogenesis, neural migration, growth, differentiation, survival, and death.28 These effects occur largely
as a consequence of the ability of gonadal steroids to
modulate genomic transcription. As transcriptional
regulators, the receptors for gonadal steroids direct or
modulate the synthesis of the synthetic and metabolic
enzymes as well as receptor proteins for many neurotransmitters and neuropeptides.29 The advances of the
past 15 years, however, have demonstrated that the cellular effects of gonadal steroids are far more complex
and wide-reaching than suggested by their originally
described genomic actions.
Gonadal steroids regulate cell survival. Neuroprotective
effects of E2 have been described in neurons grown in
serum-free media or those exposed to glutamate, amyloid,
hydrogen peroxide, or glucose deprivation.14 Some of
these effects appear to lack stereospecificity (i.e. are not
classical receptor-mediated effects) and may be attributed to the antioxidant properties of E2,30,31 although
data from one report are consistent with a receptormediated effect.32 Gonadal steroids may also modulate
cell survival through effects on cell survival proteins
(e.g. Bcl-2, BAX), MAPK, Akt or even amyloid precursor protein metabolism.22,23,33,34
Some actions of gonadal steroids on brain appear to
be context- and developmental stage-dependent. ToranAllerand35 has shown that estrogen displays reciprocal

interactions with growth factors and their receptors
(e.g. p51 and neurotrophins, trkA) in such a way as to
regulate, throughout development, the response to estrogen stimulation: estrogen stimulates its own receptor
early in development, inhibits it during adulthood,
and stimulates it again in the context of brain injury.
Additionally, we have demonstrated that the ability to
modulate serotonin receptor subtype and GABA receptor subunit transcription in rat brain with exogenous
administration of gonadal steroids or gonadal steroid
receptor blockade is largely dependent on the developmental stage (e.g. last prenatal week vs fourth postnatal
week) during which the intervention occurs36 (Zhang et al,
unpublished data).
Finally, the effects of gonadal steroids do not occur
in isolation but, rather, in exquisite interaction with the
environment. Juraska,37 for example, demonstrated that
the rearing environment (enriched vs impoverished) dramatically influences sex differences in dendritic branching in the rat cortex and hippocampus. Further, the size
of the spinal nucleus of the bulbocavernosus and the
degree of adult male sexual behavior in rats is in part
regulated by the amount of anogenital licking they receive
as pups from their mothers, an activity that is elicited
from the dames by the androgen the pups secrete in
their urine.38
The vicissitudes of gonadal steroids and their receptors, therefore, both direct neural architecture and provide
the means by which the response of the central nervous
system (CNS) to incoming stimuli may be altered. The
extent to which these effects underlie or contribute to
differential pharmacological efficacy or behavioral differences observed across individuals is unclear but is of
considerable potential relevance for PMS and other
reproductive endocrine-related mood disorders.

ROLE OF OVARIAN STEROIDS IN
MODULATING THE SYSTEMS INVOLVED
IN AFFECTIVE ADAPTATION AND
PREMENSTRUAL SYNDROME
Neuroregulation
Results from animal studies demonstrate that ovarian
steroids influence several of the neuroregulatory systems
thought to be involved in both the pathophysiology of
affective disorders and PMS.39–41 Preclinical studies have
documented the myriad of effects of ovarian steroids
on neurotransmitter system activities, including regulation of synthetic and metabolic enzyme production as well
as receptor and transporter protein activity. The modulatory effects of ovarian steroids on the serotonin (5hydroxytryptamine; 5-HT) system have been extensively

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studied, reflecting in part interest in the higher prevalence of depression in women and the efficacy of selective serotonin reuptake inhibitors in PMS. In some, but
not all (reviewed in Rubinow et al42), experimental paradigms, estradiol has been observed to inhibit serotonin
reuptake transporter (SERT) mRNA,43 decrease activity
of the 5HT1A receptor (down-regulation and uncoupling from its G protein),44,45 increase 5-HT2A46 receptor
binding and mRNA,47 and facilitate imipramine-induced
down-regulation of 5-HT2 receptors in the rat frontal
cortex, an action seen to accompany antidepressant administration.48 5HT1A receptor binding, which is decreased
in depression, is modulated by both estradiol14,49–53 and
progesterone.54–57 Similarly, SERT message, protein,
and binding have been reported to be changed by
ovarian steroids in preclinical studies.42,43,57–60
In humans there are patterns of effects of ovarian
steroids on the serotonin system similar to those observed
in animals. Menstrual cycle phase effects on the concomitants of serotonergic stimulation include an increased
prolactin secretion during the luteal phase after mchlorophenylpiperazine (m-CPP)61 and buspirone62
administration compared to the early follicular phase,
and a decreased prolactin response following L-tryptophan63 or d-fenfluramine64 compared to mid-cycle. Indeed,
prolactin secretion is increased after progesterone
administration in women with gonadotropin-releasing
hormone (GnRH) agonist-induced hypogonadism.65
Finally, although the effect of estrogen on 5-HT1A receptor binding has not been examined in humans, one
uncontrolled study reported an increase in 5-HT2A
binding (18F altanserin) in the anterior cingulate, dorsolateral prefrontal cortex, and lateral orbital frontal
cortex during combined estrogen and progestin replacement (but not after estradiol alone).66
Finally, several non-classical neural signaling systems
have been identified as potential mediators of the therapeutic actions of antidepressants and electroconvulsive
therapy (ECT) (e.g. c-AMP response element-binding
protein [CREB] and brain-derived neurotrophic factor
[BDNF]67) based on observations that these systems are
modulated by a range of therapies effective in depression (e.g. serotonergic and noradrenergic agents and
ECT) and exhibit a pattern of change consistent with
the latency to therapeutic efficacy for most antidepressants.68 For example, antidepressants increase the expression and activity of CREB in certain brain regions (e.g.
hippocampus)69 and regulate (in a brain region-specific
manner) activity of genes with a cAMP response
element.68 Genes for BDNF and its receptor trkB have
been proposed as potential targets for antidepressantrelated changes in CREB activity.68 Similarly, estradiol
has been reported to influence many of these same neuroregulatory processes. Specifically, ovariectomy has been

reported to decrease, and estradiol increase, BDNF
levels in the forebrain and hippocampus.70 Estrogen
also increases CREB activity,71 trkA,72 and decreases
GSK-3␤ activity (Wnt pathway)73 in the rat brain,
changes similar to those seen with mood stabilizer
drugs. In contrast, an estradiol-induced decrease in
BDNF has been reported to mediate estradiol’s regulation
of dendritic spine formation in hippocampal neurons.74
Thus, the therapeutic potential of gonadal steroids in
depression is suggested not only by their widespread
actions on neurotransmitter systems but also by certain
neuroregulatory actions shared by both ovarian steroids
and traditional therapies for depression (i.e. antidepressants, ECT).

Neurocircuitry
Several studies have employed neuroimaging techniques
(i.e. positron emission tomography [PET] or functional
magnetic resonance imaging [fMRI]) to examine the
effects of ovarian steroids or the normal menstrual
cycle on regional cerebral blood flow under conditions of
cognitive activation. For example, using PET (H215O)
Berman et al75 employed the Wisconsin Card Sort Test,
a measure of executive function and cognitive set shifting, and observed that both estradiol and progesterone
regulated cortical activity in brain regions (prefrontal
cortex, parietal and temporal cortex, and hippocampus) also reported to be involved in the regulation of
mood. Similarly, Shaywitz et al76 reported, in a randomized, double-blind, placebo-controlled crossover
trial, that postmenopausal women did not perform differently on estrogen therapy (ET) compared with
placebo, but fMRI during ET showed significantly
increased activation in the inferior parietal lobule and
right superior frontal gyrus during verbal encoding,
with significant decreases in the inferior parietal lobule
during non-verbal coding. More recently, fMRI studies
have documented menstrual cycle phase-related changes
in the activities of several brain regions involved in the
neurocircuitry of both arousal and reward processing,
including the amygdala, orbitofrontal cortex, and striatum.77,78,209 Although the brain regions potentially regulated by estrogen are inadequately characterized, the
activities in the frontal cortex and hippocampus, areas
subserving memory and the regulation of affect, appear
to be regulated by ovarian steroids.

in ovariectomized animals,79–82 whereas higher doses
and longer treatment regimens enhance HPA axis reactivity to stressors.83–85 The regulatory effects of changes
in reproductive steroids or menstrual cycle phase on the
HPA axis in women are less well studied. Although some
studies using psychological stressors identified increased
stimulated cortisol in the luteal phase,86,87 others using
psychological88,89 or physiological (e.g. insulin-induced
hypoglycemia, exercise)90,91 stressors failed to find a
luteal phase increase in HPA axis activity.
Altemus et al92 recently demonstrated that exercisestimulated HPA responses were increased in the midluteal compared with the follicular phase. However, in
contrast to a large animal literature documenting the
ability of estradiol to increase HPA axis secretion, Roca
et al93 found that progesterone, but not estradiol, significantly increased exercise-stimulated arginine vasopressin (AVP), adrenocorticotropic hormone (ACTH),
and cortisol secretion compared with a leuprolide-induced
hypogonadal condition or estradiol replacement. The
mechanism by which progesterone augments stimulated HPA axis activity is currently unknown but could
include the following: modulation of cortisol feedback
restraint of the axis;79,94–97 neurosteroid-related downregulation of GABA receptors;98 and up-regulation of
AVP (consistent with luteal phase reductions in the
threshold for AVP release).99 Alternatively, Ochedalski
et al suggest that progesterone enhances oxytocininduced corticotropin-releasing hormone (CRH).210

ENDOCRINE STUDIES IN PREMENSTRUAL
SYNDROME
Effects of hormone ‘replacement’ therapies
Despite the lack of evidence of ovarian dysfunction in
women with PMS, the view that an abnormality of
corpus luteum function caused PMS endured, largely
because of the temporal association of PMS symptoms
with the luteal phase of the menstrual cycle. Thus, multiple trials were conducted involving the administration
of progesterone or progestin in women with PMS.100
The widespread use of progesterone in women with
PMS was considerably diminished, however, by the
results of several recent studies. First, two large doubleblind, placebo-controlled trials of natural progesterone
(both suppository and oral forms) definitively demonstrated the lack of efficacy of progesterone compared
with placebo in PMS.101,102 Secondly, a study employing a progesterone receptor antagonist, RU-486, with or
without human chorionic gonadotropin demonstrated
that the normal symptoms of PMS could occur independent of the luteal phase of the menstrual cycle103

and, therefore, a luteal phase abnormality as a cause of
PMS was no longer tenable.
The belief that PMS reflected a disturbance in
ovarian function led to several trials of oral contraceptives (OCs) to suppress or regulate ovarian function in
this condition. Earlier cross-sectional studies suggested
that women using OCs experienced fewer PMS symptoms than non-users,104–106 although opposite results
were also reported.107 Most studies demonstrated that
women on OCs reported fewer physical symptoms
(i.e. breast pain, bloating) but did not report fewer
or less severe mood symptoms than non-users.108–110
In fact, similar prevalence rates of cyclic mood symptoms, regardless of OC use, were prospectively documented by Sveindottir and Backstrom,111 with 2–6%
of women meeting criteria for severe PMS in both OC
users and non-users. Despite similar prevalence rates
of negative mood symptoms in OC users and nonusers, some clinic-based studies suggested that a subgroup of women with PMS reported an improvement
in mood symptoms while on OCs.112–117 Results of
recent controlled trials of OCs in PMS parallel those
of the cross-sectional studies.118–120 Significant reductions in symptom severity on OCs compared with
placebo were observed, however, for some physical and
behavioral symptoms, including loss of libido,119 breast
pain, and bloating,118 and increased appetite and food
cravings.120 Thus, with one recent exception,121 neither
cross-sectional studies nor controlled trials support a
role for any formulation of OCs (tested to date) in
the treatment of PMS.
The efficacy in PMS of estradiol (without the progestin contained in OCs) and testosterone have also been
tested. Trials of supraphysiological doses of estradiol
with or without testosterone have documented beneficial effects compared with placebo in women with
PMS.122–124 Preliminary reports suggest that lower
(more physiological) doses of testosterone alone may
also be effective in the treatment of PMS.125–127 Lower
doses of estrogen, however, are not more effective than
placebo128 and, therefore, it is possible that the therapeutic benefits of the higher-dose estrogens are secondary to the suppression of ovulation.124 Nevertheless,
one cannot infer the efficacy of these compounds to
be secondary to ovarian suppression alone, given the
lack of efficacy of OCs which also inhibit ovulation, and
the reported efficacy of compounds such as danazol129
when administered after ovulation in at least one study.130

Basal hormone studies
As noted above, the temporal coincidence of symptoms
and the luteal phase in women with PMS led to the
presumption that reproductive endocrine function was

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disturbed in these patients. Comparisons of basal plasma
hormone levels in women with PMS and controls,
however, have revealed no consistent diagnosis-related
differences. Specifically, we observed no diagnosis-related
differences in the plasma levels, areas under the curve
(AUCs), or patterns of hormone secretion for estradiol,
progesterone, follicle-stimulating hormone (FSH), or
luteinizing hormone (LH),131 findings consistent with
those of Backstrom et al132 comparing patients with high
and low degrees of cyclical mood change. In subsequent
additions to the conflicting literature, Wang et al133
observed increased estradiol and decreased progesterone
levels in women with PMS, Redei and Freeman134
reported non-significant increases in both estradiol and
progesterone, and Facchinetti et al135 found no differences from controls in integrated progesterone levels.
Results for studies of androgen levels have been similarly inconsistent, demonstrating both normal and
decreased testosterone levels136–138 and elevated and
decreased free testosterone levels.137,138 Abnormalities
of gonadotropin secretion have been observed (albeit
inconsistently) in several studies, with reports of both
higher139 and lower140 mid-luteal plasma FSH levels,
delayed follicular development and prolonged follicular phase after corpus lute-ectomy140 suggestive of
decreased FSH or increased inhibin secretion, and no
diagnosis-related differences in plasma LH133,139–141
but a correlation in women with PMS between higher
LH levels and more severe symptoms. In summation,
then, there is no consistent or convincing evidence that
PMS is characterized by abnormal circulating plasma
levels of gonadal steroids or gonadotropins or by
hypothalamic–pituitary–ovarian (HPO) axis dysfunction. Several studies do, however, suggest that levels of
estrogen, progesterone, or neurosteroids (e.g. pregnenolone sulfate) may be correlated with symptom
severity in women with PMS (see below).133,142,143
Recent speculations about the etiology of PMS have
focused on putative abnormal neurosteroid levels.
Observations central to these speculations include the
following:
1.

2.

3.

The GABA receptor (the presumed mediator of
anxiolysis) is positively modulated by the 5a- and
5b-reduced metabolites of progesterone (allopregnanolone and pregnanolone, respectively).10
Withdrawal of progesterone in rats produces anxiety
and insensitivity to benzodiazepines due to withdrawal of allopregnanolone, with consequent
induction of GABAA ␣4 subunit levels and inhibition of GABA currents.98,144
Allopregnanolone displays anxiolytic effects in several
animal anxiety models145–147 and may be involved
in the stress response.148

4.

5.

6.

7.

Decreased plasma allopregnanolone levels are seen
in major depressive disorder and in depression
associated with alcohol withdrawal, with an increase
in levels seen in plasma and cerebrospinal fluid (CSF)
following successful antidepressant treatment.149–152
Antidepressants may promote the reductive activity of one of the neurosteroid synthetic enzymes
(3␣-HSOR), thus favoring the formation of allopregnanolone.153
PMS patients show differences in pregnanolonemodulated saccadic eye velocity (SEV) and sedation in the luteal phase compared with controls154
(although the reported differences seem attributable to an SEV response to vehicle in those with
PMS and a blunted sedation response in the follicular phase in controls).
High-severity PMS patients show blunted SEV and
sedation responses to GABAA receptor agonists –
pregnanolone154 or midazolam155 – compared with
low-severity PMS patients.

Whereas one investigator observed decreased serum
allopregnanolone levels in women with PMS compared
with controls on menstrual cycle day 26,156 other studies
showed no diagnosis-related differences in allopregnanolone or pregnanolone,133,157 nor any difference
in allopregnanolone levels in women with PMS before
and after successful treatment with citalopram.158 Wang
et al133 did find that if two cycles differed in the AUC
of a hormone by more than 10%, the cycle with the
lower levels of allopregnanolone and higher levels of E2,
pregnanolone, and pregnenolone sulfate was accompanied by higher levels of symptom severity. Additionally,
in a study in which progesterone was administered
to women with leuprolide-suppressed ovarian function, women with PMS, but not comparison women,
showed a significant relationship between symptom
development and declining allopregnanolone levels
during progesterone administration.
Studies of a variety of other endocrine factors in
patients with PMS have been similarly unrevealing. In
general, no differences have been observed in basal
plasma cortisol levels, urinary free cortisol, the circadian pattern of plasma cortisol secretion, or basal
plasma ACTH levels.159 (Both decreased ACTH levels
in PMS patients across the menstrual cycle and no differences from controls have been reported.138,160,161)
Similarly, studies of other hormones have done little to
elucidate the cause of PMS. Despite the appearance of
abnormal baseline thyroid function in 10% of our
subjects and abnormal (both blunted and exaggerated)
thyroid-stimulating hormone (TSH) response to
thyrotropin-releasing hormone (TRH) in 30% of our
subjects, the vast majority of patients with PMS have

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normal hypothalamic–pituitary–thyroid axis function.162
Luteal phase decreases in both plasma ␤-endorphin163,164
and platelet serotonin uptake165,166 have been reported
in PMS; neither the diagnostic group-related decreases
nor their confinement to the luteal phase are consistently observed.138,167–170 Finally, in a study of CSF,
Eriksson et al171 observed no differences in CSF monoamine metabolites in PMS patients compared with controls, nor were there menstrual cycle-related differences
in either group. Similarly, Parry et al172 found no cyclerelated differences (midcycle vs premenstrual) in CSF
ACTH, ␤-endorphin, GABA, 5-hydroxyindoleacetic acid
(5-HIAA), homovanillic acid (HVA), or norepinephrine; a slight but significant premenstrual increase in CSF
3-methoxy-4-hydroxyphenyl glycol (MHPG) was noted.
Even if these differences are confirmed, their persistence across the menstrual cycle would appear to argue
against their direct role in the expression of a disorder
confined to the luteal phase. Presently, then, there is no
clearly demonstrated luteal phase-specific physiological
abnormality in PMS.

Dynamic studies of hormone secretion
Several strategies have been employed to assess hypothalamic and pituitary function in women with PMS.
First, basal plasma levels of gonadotropins have been
measured across the menstrual cycle in women with
and without PMS. Efforts to distinguish hypothalamic
function from that of the pituitary led to studies of LH
pulsatility (i.e. the frequency of LH pulses rather than
mean LH levels). Additionally, evidence that endogenous opiate peptides modulated GnRH/LH secretion
during the early- and mid-luteal phase of the menstrual
cycle, when PMS symptoms appear, prompted the use
of pharmacological challenges with opiate antagonists
to indirectly evaluate the level of central opiate tone.
(Alterations in the amount of disinhibition of LH secretion after the administration of an opiate antagonist
could suggest differences in the secretion of endogenous
opiates that may be relevant to the development of
PMS symptoms.) Finally, acute GnRH challenge studies
have been employed to evaluate stimulated gonadotropin
secretion and, possibly, identify differences in hypothalamic or pituitary feedback mechanisms and pituitary
gonadotropin reserve.173
The pattern of pulsatile secretion of LH has been characterized in women with and without PMS, employing
serial blood sampling (e.g. every 10 minutes) during the
luteal phase of the menstrual cycle. Facchinetti and
coworkers135,174 observed diagnostic differences in the
pattern of pulsatile secretion of LH during the luteal
phase: women with PMS had an increased frequency
and a decreased amplitude and duration of both LH and

progesterone secretion compared with controls, suggesting a reduced level of opioid inhibition of LH (frequency) in PMS during the luteal phase as well as the
possibility of decreased pituitary responsiveness (LH
amplitude) compared with women without PMS.
However, two subsequent studies could not confirm
this finding.175,176 Similarly, two studies177,178 using
single-dose administration of naloxone failed to identify differences between the pattern of secretion of LH
after naloxone during the mid-luteal phase in women
with PMS compared with controls, suggesting the absence
of differences in the central opioid tone in these two
groups of women. However, Rapkin et al179 employed
a continuous infusion of naloxone in the mid-luteal
phase and observed a significantly blunted LH response
to naloxone. These authors suggested that prolonged
opiate antagonism was necessary to reveal the abnormal central opioid tone during the mid-luteal phase in
women with PMS. If these findings are confirmed, it is,
nonetheless, premature to suggest that the differences
in naloxone-induced LH secretion reflect a deficiency
of central opiate functions in PMS. Indeed, as suggested
by Rapkin,179 the regulatory effects of endogenous
opiates, progesterone, and progesterone’s neurosteroid
metabolites on GnRH secretion are part of a complex
physiological system180,181 and not easily translated, at
this point, into a pathophysiology of PMS.
Four studies have performed GnRH stimulation with
100 or 10 ␮g doses of GnRH in women with PMS and
controls.177,178,182,183 No differences have been reported
in the pattern of gonadotropin secretion in single tests
during either the luteal178 or the follicular phase.177 In
one study in which GnRH stimulation tests were
performed in both follicular and luteal phases, blunted
progesterone and allopregnanolone secretion after 100 ␮g
of GnRH were observed in women with PMS compared with a group of asymptomatic controls,182 but
gonadotropin levels were not reported, and hence the
source of the blunted progesterone cannot be identified.
The above-noted study by Facchinetti et al178 observed
lower GnRH-stimulated LH secretion in five women
with PMS than in four controls. Although the observed
LH AUC was not significantly different across diagnostic
groups, the calculated effect size (1.05) between groups
was moderate and suggested that their findings could
reflect a type II error. We used a supraphysiological
dose of GnRH in a larger sample size and, similar to
Facchinetti’s results, women with PMS were not distinguished from controls by an abnormal LH or FSH
response to GnRH stimulation. Our data and those of
others, then, document no abnormalities of gonadotropin
secretion in response to acute GnRH stimulation in
women with PMS. These data also provide indirect evidence of normal HPO feedback during the follicular and

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mid-luteal phases of the menstrual cycle in this condition
as well. Overall, extant data do not support a dynamic
disturbance of the HPO axis in women with PMS.

Manipulations of menstrual cycle
physiology
Given the absence of basal or stimulated reproductive
endocrine abnormalities or luteal phase-specific biological abnormalities in PMS, one could reasonably ask
whether the luteal phase is required for the expression
of PMS. We103 answered this question by blinding
women with PMS to menstrual cycle phase with the
progesterone antagonist mifepristone (RU-486) combined with either human chorionic gonadotropin (hCG)
or placebo. Mifepristone administered alone 7 days
after the mid-cycle LH surge precipitated menses and
the premature termination of the luteal phase, while the
addition of hCG preserved the luteal phase even after
the mifepristone-induced menses. Consequently, following the mifepristone-induced menses, patients did
not know whether they were in the follicular phase of
a new cycle (mifepristone alone) or in the preserved
luteal phase of the first cycle (mifepristone ⫹ hCG). We
observed that women with PMS experienced their characteristic premenstrual mood state after the mifepristone-induced menses in both groups, despite the presence
of an experimentally induced follicular phase in the
women receiving mifepristone alone. The mid to late
luteal phase, then, is clearly not required for the appearance of PMS symptoms. Nonetheless, it remained possible that symptoms could be triggered by hormonal
events prior to the mid to late luteal phase, consistent
with reports that the suppression of ovulation results in
a remission of PMS symptoms.184,185
Studies employing different methods to suppress or
eliminate ovarian function (e.g. GnRH agonists, the
synthetic androgen danazol, or oophorectomy) have
consistently demonstrated the therapeutic efficacy of
ovarian suppression in PMS. As noted above, however,
it is difficult to ascribe the efficacy of these treatments
solely to ovarian suppression, given the lack of efficacy
of oral contraceptives (which inhibit ovulation)118 and
the reported efficacy of danazol when administered after
ovulation.186 Administration of an OC does of course
introduce a new estrogen/progestogen cycle, which could
explain the persistence of symptoms despite ovulation
suppression. Recently, we confirmed the efficacy shown
by others of GnRH agonists (e.g. leuprolide acetate
[Lupron]) in the treatment of PMS.185,187–190 Consistent
with Bancroft’s187 earlier observations, a therapeutic
response was not observed in all patients despite the
consistent reduction of gonadal steroids to hypogonadal levels. While the majority of study participants

did show a therapeutic response (10/18), the mechanism of action remained unclear (e.g. low plasma
gonadal steroid levels, consistent gonadal steroid levels,
anovulation, suppression of follicular development). This
uncertainty was in part addressed by the double-blind,
placebo-controlled reintroduction of estradiol (0.1 mg
Estraderm patch) or progesterone (200 mg bid by suppository) in the study participants in whom Lupron displayed efficacy. The results unequivocally demonstrated
the precipitation of a wide range of characteristic
symptoms of PMS during both estrogen and progesterone add-back but not during placebo add back
(Figure 10.2). Both Muse191 and Mortola et al189 previously described the return of symptoms during 1month trials of estrogen, progestin, or placebo, although
symptom return was not seen by Mortola et al with
the combination of estrogen and progestin. Despite the
questions raised by Mortola’s study – Why was placebo
as able to induce the return of behavioral symptoms as
were the gonadal steroids? Why did solitary gonadal
steroids precipitate the return of symptoms but sequential administration fail to stimulate symptom return? –
the combined results from our study and those of
Muse191 and Mortola189 strongly suggest the role of
gonadal steroids in the occurrence of PMS symptoms.
Particularly striking, however, is the observation that
control subjects lacking a history of PMS and going
through the same protocol (i.e. Lupron-induced hypogonadism followed by gonadal steroid add-back)
showed no perturbation of mood during hypogonadism and no mood disturbance during hormonal
add-back (see Figure 10.2). It would appear, therefore,
that women with a history of PMS are differentially
sensitive to the mood-perturbing effects of gonadal
steroids, as similar steroid manipulations in women
without a history of PMS are without effect on mood.
This differential sensitivity may also be consistent with the
observations mentioned earlier that PMS symptoms are
correlated with progesterone levels in women with PMS
despite mean levels in patients that are not different from
those in controls.

OTHER NEUROBIOLOGICAL SYSTEMS
IMPLICATED IN THE PATHOPHYSIOLOGY
OF PREMENSTRUAL SYNDROME
Hypothalamic–pituitary–adrenal axis
Observations of both numerous reciprocal regulatory
interactions between the stress and reproductive axes
and abnormal HPA axis activity in depression suggested that dysregulation of the stress response in
women with PMS may contribute to their susceptibility

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Most

3

Sadness

92 THE PREMENSTRUAL SYNDROMES

2

Least

1
Week

Women with premenstrual syndrome

1

2

3

4

5

6

7

8

1

Leuprolide alone

Sadness

Most

Least

3

2

3

4

1

E2 + leuprolide

2

3

4

P4 + leuprolide

Normal women

2

1
Week

1

2

3

4

5

6

7

8

Leuprolide alone

1

2

3

E2 + leuprolide

4

1

2

3

4

P4 + leuprolide

Figure 10.2 Ten women with premenstrual syndrome and 15 controls had minimal mood and behavioral
symptoms during Lupron (leuprolide acetate). In contrast, women with premenstrual syndrome but not the
controls had a significant increase in sadness during either estradiol (E2) or progesterone (P4) administration.
Histograms represent the mean (⫾ SE) of the seven daily scores on the daily rating form sadness scale for each of
the 8 weeks preceding hormone replacement (Lupron alone) and during the 4 weeks of Lupron ⫹ E2 and Lupron
⫹ P4 replacement. A score of 1 indicates that the symptom was not present and a score of 6 indicates that it was
present in the extreme.

to affective disturbance. While studies of basal HPA
axis function have been unrevealing, studies of stimulated HPA axis activity provide evidence of the involvement of this neuroendocrine axis in PMS. In a recent
study, Roca et al93 showed a differential HPA axis
response to exercise stimulation in women with PMS
compared with controls. Women with PMS fail to show
the luteal phase increase in stimulated AVP, ACTH, and
cortisol seen in normal women and additionally display
adrenal hyporesponsivity. As it is progesterone rather
than estradiol that enhances exercise-stimulated HPA
activity,93 women with PMS appear to display an
abnormal response to progesterone. A variety of data

support these observations. In a prior study,61 we
showed that m-CPP-stimulated cortisol was significantly blunted in the luteal (but not the follicular)
phase in women with PMS, consistent with the current
findings as well as with data from Girdler et al192
showing decreased luteal phase-stimulated cortisol in
women with PMS. Additionally, blunted or absent cortisol response to CRH or naloxone, respectively, was
observed in the luteal phase in women with PMS.193 In
a separate earlier study,194 we showed that women with
PMS display low evening cortisol levels across the menstrual cycle; this was also seen by Parry et al195 and
Odber et al196 and is consistent with either adrenal

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PATHOPHYSIOLOGY I: ROLE OF OVARIAN STEROIDS 93

hyposensitivity or altered circadian cortisol dynamics
(although, see Parry et al197 and Steiner et al198).
Bancroft et al63 identified blunted levels across the
menstrual cycle of tryptophan-stimulated cortisol secretion in women with PMS. Finally, an abnormal response
to (presumed) luteal phase progesterone in women with
PMS was also seen in their failure to manifest the normal
luteal phase alteration in the timing of the cortisol
acrophase.195 These data, then, suggest the following:
●

●

●

●

stimulated cortisol (albeit paradigm specific) is
decreased in women with PMS relative to controls
during the luteal phase
the adrenal response to ACTH may be blunted in
women with PMS
women with PMS manifest an abnormal HPA axis
(and mood) response to progesterone
women with PMS display disturbances of the HPA
axis that are markedly different from those identified in major depression.

Although the determinants of these observations are
unclear, they provide another compelling example of
differential response to gonadal steroids in women with
PMS and suggest an additional potential source of vulnerability to affective disturbance.

Serotonin
Serotonin (5-HT) plays a role in the regulation of mood,199
impulsivity,200 appetite,201 sleep,202 and sexual interest,203 behaviors that vary during the menstrual cycle in
women with PMS. Studies of serotonin measures and
the efficacy of serotonergic agonists further suggest the
relevance of the serotonin system for PMS and are
reviewed in Chapters 3 and 9.

CONCLUSIONS
In order to identify what the study of PMS may contribute to our understanding of the effects of gonadal
steroids on brain and behavior, several observations
must be integrated. First, PMS does not reflect a disturbance of reproductive endocrine function. Secondly,
estrogen and progesterone appear to be capable of triggering mood disturbances in a susceptible population;
i.e. some pre-existing vulnerability must explain the
capacity of the same biological stimulus (e.g. gonadal
steroids) to elicit a differential behavioral response
across groups of people. Thirdly, perturbations of nonreproductive endocrine systems may precipitate PMS.
For example, PMS may appear in the context of
hypothyroidism (with symptoms responsive to thyroid

hormone replacement),204 and both provocative61,205
and especially treatment studies206 suggest the relevance
of the serotonin system to PMS. PMS, then, may represent a behavioral state that is triggered by a reproductive endocrine stimulus in those who may be rendered
susceptible to behavioral state changes by antecedent
experiential events (e.g. history of major depression207
or physical or sexual abuse208) or biological conditions
(e.g. hypothyroidism).204 Treatment can, therefore, be
directed to either eliminating the trigger (e.g. ovarian
suppression) or correcting the ‘vulnerability’ (e.g. serotonergic antidepressants).206 Although the means by
which alterations in gonadal steroids trigger changes in
behavioral state in certain individuals are unclear, it is
nonetheless striking that, in contrast to the pathological function of other endocrine systems (e.g. adrenal,
thyroid) seen in association with mood disorders, gonadal
steroids may precipitate mood disturbances in the context
of normal ovarian function. This suggests that further
study of the interactions between gonadal steroids and
other neuroactive systems may help elucidate general
mechanisms underlying affective regulation as well as
the physiological substrate that predisposes certain people
to experience reproductive endocrine-related mood
disorders.

ACKNOWLEDGMENT
The research was supported by the Intramural Research
Programs of the NIMH.

INTRODUCTION
In the more than quarter of a century since the introduction of nuclear magnetic resonance (NMR) techniques to the armamentarium of the scientist exploring
the inner workings of the human brain, relatively few
neuroimaging studies have focused on the interplay
between gonadal steroids, neurochemistry, and brain
function. Nowhere is this void more obvious than when
it comes to examining the role of hormonal fluctuations in disorders associated with reproductive function
such as premenstrual syndrome (PMS)/premenstrual
dysphoric disorder (PMDD), postpartum depression,
or mood changes occurring during the menopause or
with the use of steroid contraceptives. Indeed, the vast
majority of studies utilizing NMR and other imaging
techniques such as positron emission tomography
(PET) and single-photon emission computed tomography (SPECT) to study women under various hormonal
conditions, focus, not on the brain, but on the breast,
uterus, and ovaries.
With the recent advancements in proton magnetic
resonance spectroscopy (1H-MRS), which allows the
non-invasive quantification of important amino acid
neurotransmitters such as ␥-aminobutryic acid (GABA)
and glutamate,1 has come the opportunity to gain
unprecedented access to brain chemistry in living
human subjects. As reviewed by Backstrom and colleagues in Chapter 13 of this book, progesterone modulation of GABAergic function via its neurosteroid
metabolite allopregnanolone (ALLO) is likely to be
critical to the pathogenesis, and perhaps treatment, of
PMS/PMDD. Additionally, Backstrom points out that
estrogen, which has antidepressant effects in some populations, also contributes to mood deterioration when
paired with certain doses of progesterone. Estrogen

enhances N-methyl-D-aspartate (NMDA) receptor
function,2 and alters glial morphology and function in
a manner that may impact removal of glutamate from
the synaptic cleft (reviewed by McEwen,3 GarciaSegura and McCarthy,4 Pawlak et al,5 and Mong and
Blutstein6). That both ovarian hormones are likely to
be powerful modulators in the balance between neuronal excitation and inhibition sets in bold relief the
unique promise that MRS holds as a neuroimaging
technique to further our understanding of the neuroendocrine milieu that leads to negative affect.
This present chapter provides a brief overview of
neuroimaging studies that have examined menstrual
cycle and/or hormonal modulation of brain chemistry
and/or function. A particular emphasis will be placed
on exploring the role of GABA and glutamate in
PMS/PMDD and how neuroimaging techniques such as
MRS can be further exploited to enhance our understanding of the neurosteroid–GABA interplay in
neuropsychiatric disorders in women.

NEUROIMAGING STUDIES OF THE
MENSTRUAL CYCLE
Although there are as yet few studies involving PMDD
patients, there have been several neuroimaging studies
focusing on changes across the menstrual cycle in
healthy participants. One early PET study, for example,
showed that regional cerebral blood flow (rCBF)
during a prefrontal cortex-dependent task was attenuated by pharmacological ovarian suppression, but
normalized with estrogen or progesterone replacement.7 Neither behavioral response nor brain activation during a control task was affected by these
manipulations, suggesting that ovarian steroids have a

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100 THE PREMENSTRUAL SYNDROMES

significant effect on prefrontal cortical activation
during cognition.
Functional magnetic resonance imaging (fMRI)
studies evaluating cognition have suggested little
change in the location of activation across phases of the
cycle, although some have found greater activation
during high levels of estrogen or estrogen and progesterone. One study utilized a word-stem completion
task, a mental rotation task, and a simple motor task
(Table 11.1).8 There were no differences between male
and female subjects when females were scanned during
the low estrogen phase, but during the periovulatory
phase of high estrogen, women exhibited a marked
increase in activation of cortical areas involved in the
cognitive tasks, but not the motor task. Similarly, the
luteal phase was marked by greater recruitment of
brain regions involved in a semantic decision task than
the early follicular phase.9 Another study involving
rhyme identification did not find differences in the
regions that were activated during the follicular and

luteal phases.10 It is difficult in the absence of behavioral effects to determine whether increased activation
during relatively high levels of estradiol and progesterone is the result of their direct effects on cognition or
a result of other influences on the BOLD (blood oxygenation level dependent) signal, such as vascular
effects.11 Even when differences in activation exist in
cognitive tasks of interest and not simple control tasks,
it is possible that differences in cerebral vasculature in
the regions activated by the control task may influence
findings.8 Thus, precise control conditions are required
to evaluate changes in brain activation during cognition
that coincide with changes in ovarian steroid levels.
Studies have also evaluated changes in affective processing across the menstrual cycle in healthy women by
comparing activation to emotional vs neutral stimuli.
These data may be useful in identifying abnormalities
in women with PMDD. One study reported increased
activation in several cortical and subcortical regions,
including areas of the brainstem, hippocampus,

Activation areas larger during high hormones for
a semantic but not perceptual task

Goldstein et al12

12 healthy women scanned twice; early
and late follicular phases

Increases activation in response to unpleasant
visual stimuli during the early follicular phase
(presumed low hormones) in several regions of
interest; hormone levels were not obtained to
verify phases of interest

Increased activation in regions of interest during
response inhibition to positive words in the
luteal phase. Activation correlating with luteal
phase estradiol level was dissociated by valence

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PATHOPHYSIOLOGY II: NEUROIMAGING, GABA, AND THE MENSTRUAL CYCLE 101

orbitofrontal cortex (OFC), and anterior cingulate
cortex (ACC), in response to unpleasant images during
low hormones compared to presumed high estrogen
levels.12 Thus, it is possible that high estrogen levels may
decrease activation to negative stimuli, and possibly
reduce their salience. However, hormone levels were
not obtained, limiting inferences based on ovarian
hormone effects. In addition, it was hypothesized that
decreases in activation to aversive stimuli specifically
related to the stress response,12 but estrogen has also
been associated with enhancing hypothalamic–pituitary–
adrenal (HPA) axis function.13,14 More research is necessary to investigate the pathway of estrogen’s effects
and to explore whether menstrual cycle phase may
have influenced activation to unpleasant images through
a mechanism not directly related to the stress response.
In a recent study from our laboratory, we utilized an
emotional go/no-go task to evaluate menstrual cyclerelated changes in response inhibition.15 In each condition, participants were instructed to respond to one
type of stimulus (e.g. positive words) but to ignore
another type (e.g. neutral words). Compared with the
follicular phase of low hormone levels, we found significantly increased activation in the ACC and dorsolateral prefrontal cortex (DLPFC) while inhibiting
response to positive words (compared with when inhibiting response to neutral words) during the luteal phase
of high estrogen and progesterone levels.15 In addition,
luteal phase DLPFC activation during response inhibition to positive words was significantly positively correlated with plasma estradiol level and activation in the
caudate and inferior parietal gyrus during response
inhibition to negative words was negatively correlated
with estradiol. Thus, in healthy women, high estrogen
levels during the latter half of the menstrual cycle may
increase salience of positive stimuli and decrease
salience of negative stimuli.
In order to begin evaluating differences in brain activation during emotional processing in healthy women
compared to women with PMDD, one previous fMRI
study assessed activation in healthy women during the
late luteal phase (when PMDD symptoms are evinced)
and mid-follicular (non-symptomatic) phase.16 A variation of the emotional go/no-go task was used in which
participants were instructed to inhibit response to italicized words, including positive, negative, and neutral
stimuli. Anterior-medial OFC activation to negative
stimuli, compared with neutral stimuli, was increased
in the late luteal phase while lateral OFC activation
increased in the follicular phase.16 There were no differences in activation to positive stimuli. Because ovarian
steroids are likely to be declining in the late luteal phase
and may therefore not be very different from follicular
phase levels, hormone effects were not the primary

focus of the experiment and levels were not obtained.
Instead, these data serve to exemplify brain activation
in healthy women at these timepoints in the menstrual
cycle so that these patterns may be compared to those
with PMDD. However, in an emotional processing task
of this nature, mood is likely to have a significant
impact on behavioral response and activation. Thus, it
may be difficult to differentiate brain activation patterns resulting primarily from differences in mood
between healthy women and those with PMDD and
not the underlying disorder. Given that differences have
been found between healthy women and women with
PMDD even in the absence of symptoms (e.g. Epperson
et al17), identification of differences in brain activation
during the follicular (non-symptomatic) phase may be
more valuable than identification of emotional processing-related differences during the late luteal phase.
In contrast to fMRI studies focusing on brain structures and cognitive processes that may be modulated by
ovarian steroids, several PET, SPECT, and MRS studies
have evaluated changes in neurotransmitter systems
across the menstrual cycle in healthy women and in
women with PMDD. For example, a recent SPECT
study evaluated menstrual cycle-related changes in
dopamine transporter (DAT) availability in the striatum
and serotonin transporter availability in the brainstemdiencephalon (Table 11.2).18 No differences were
detected between the follicular and luteal phases, even
after excluding two participants who experienced anovulatory cycles in which there was no progesterone increase
in the luteal phase. However, it is possible that there
was not sufficient power to detect small changes in transporter availability in the sample of eight participants.
Similarly, one PET study found no differences in D2
dopamine receptor density, measured by putamen to
cerebellum ratios, between follicular and luteal or periovulatory phases.19 Although phase was verified by
ovarian steroid levels, sample size for this study was
small, with only four women completing tests in two
different phases (three women in the follicular and
luteal phases and one woman in early follicular and
periovulatory phases). A more recent PET study investigated the serotonin hypothesis of PMDD.20 Changes
in daily prospective ratings of mood significantly correlated with changes in brain trapping of 11C-labeled 5hydroxytryptophan (11C-5-HTP) in regions of interest
across the menstrual cycle. While changes in irritability
and depressed mood negatively correlated with changes
in trapping of the labeled serotonin precursor, changes
in happiness and energy in the follicular phase positively
correlated with changes in brain 11C-5-HTP trapping.20
Thus, it appears that a more stable cycle, marked by
little change in symptoms, is associated with an
increase in 11C-5-HTP trapping in the luteal phase, but

Changes in irritability and depressed mood
negatively correlated with changes in brain
11C-5-HTP trapping and changes in happiness and
energy positively correlated with trapping. Hormone
levels were not obtained to verify phases of interest

Single-photon emission computed tomography
Best et al18

10 healthy women scanned twice;
follicular and luteal phases

No menstrual cycle variation in striatal DAT or
brainstem-diencephalon SERT availability. Hormone
levels obtained, but Prog levels did not confirm luteal
phase in two cases

Occipital cortex GABA concentrations fluctuate
across the menstrual cycle in both healthy women
and those with PMDD. Women with PMDD have
signficantly reduced cortical GABA levels in the
follicular phase compared with healthy controls

an increase in symptoms in the luteal phase is associated with decrease in 11C-5-HTP trapping. Although
preliminary, these findings suggest a relationship
between serotonin availability and PMDD symptoms.
Using 1H-MRS to investigate the etiology of PMDD,
Rasgon et al21 found changes in neurochemistry across
the menstrual cycle. While the ratio of N-acetyl-aspartate (NAA) to creatine in the medial prefrontal cortex
was significantly lower in the luteal compared to follicular phase in all subjects, there was a non-significant
trend toward higher myoinositol to creatine ratios in

women with PMDD in the luteal phase.21 However, it
is difficult to interpret the meaning of these changing
ratios. With relatively recent advances in MRS techniques, our laboratory has been able to examine the
role of GABA, the brain’s major inhibitory neurotransmitter, in the pathogenesis of PMDD. Before we
describe our findings, it is important for the reader to
consider the preclinical and clinical evidence supporting the notion that altered GABAergic function contributes to the pathogenesis and perhaps treatment of
PMDD.

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EVIDENCE OF ALTERED GABAERGIC
FUNCTION IN PMS/PMDD
Preclinical evidence
As reviewed in Chapter 9, estrogen and progesterone
have numerous effects throughout the CNS, mediating/
modulating reproductive as well as non-reproductive
behaviors. As is true with all steroid hormones, estradiol and progesterone act through classic genomic
mechanisms, binding to intracellular receptors and
leading to gene transcription and protein synthesis over
the course of several minutes to hours to days (reviewed
by McEwen3). However, it is now well known that
estrogen and progesterone (through its metabolites)
can modulate glial and/or neuronal function within
seconds via membrane-bound ion channels.2,6,22 It is
this latter action, which is likely to be most relevant to
PMS/PMDD.
While estrogen acts directly on these membrane ion
channels, particularly those of the NMDA receptor
type,2 the effects of progesterone are primarily, if not
exclusively, mediated via its metabolites 3␣-hydroxy5␣-pregnane-20-one (allopregnanolone; ALLO) and
ALLO’s ␤-stereoisomer 3␣-hydroxy-5␤-pregnane-20one (pregnanolone; PREG) acting as potent GABAA
receptor agonists.23,24 Several studies indicate that
estrogen binding to NMDA receptors on principal
neurons in the CA1 region of the hippocampus leads to
enhanced voltage-gated Ca2+ currents2,25 and increased
dendritic spine formation. Although it is somewhat
controversial whether estrogen treatment in menopausal women enhances overall cognition,26 the positive
effects of estrogen on hippocampal-mediated cognitive
function have been well demonstrated in humans,27,28
non-human primates,29 and rodents.30,31 In addition,
estrogen appears to be critical to the maintenance of
cholinergic and catecholaminergic input to the dorsal
lateral prefrontal cortex in young adult monkeys,32
although the exact mechanism has not been fully elucidated. Estrogen treatment (ET) increases the gene and
protein expression of the astrocytic enzyme glutamine
synthase, which is important for the conversion of glutamate to glutamine.6 As glutamine is the predominant
precursor for glutamate synthesis, estradiol may
enhance overall glutamatergic function and cortical
excitability.
In contrast, ALLO and PREG exert sedative, hypnotic, and anxiolytic properties by enhancing the duration and frequency of the opening of GABAA receptor
chloride channels.22 While the seizure threshold is
lowered in proestrus when estrogen is elevated, animals
are less likely to seizure during periods of high progesterone.33 Across the estrus and menstrual cycles, ALLO

and PREG levels are thought to mirror the rise in plasma
progesterone, which occurs after ovulation. However,
ALLO and PREG are neurosteroids and, as such, can be
produced in glia and some neurons independent of
peripheral progesterone sources. Rodent studies indicate
that when under stress, the brain ratio of ALLO/progesterone is greater than that of plasma.23,34 It is thought
that adrenal production of ALLO, which is usually negligible, rises in concert with cortisol during stress states,
presumably to counteract and/or supplement some of
the stress-related effects of cortisol.35
Thus, what happens to the GABAA receptor during
the estrus and menstrual cycle, as well as during pregnancy and lactation, has become the focus of a number
of preclinical and clinical research laboratories.
Ground-breaking work from Smith and colleagues36,37
shows that acute and prolonged exposure as well as
withdrawal from ALLO results in an increase in ␣4
subunit-containing GABAA receptors, which leads to
decreased benzodiazepine sensitivity and enhanced anxiety behaviors in rodents. In contrast, progesterone and
PREG dampen the accentuation of the acoustic startle
response (ASR) in rodents undergoing corticotropinreleasing hormone (CRH) infusion into the basal
nucleus of the stria terminalis (BNST), an area of the
brain thought to mediate the effects of anxiety/stress on
the ASR.38 These data suggest that length of neurosteroid administration may contribute to varied effects
on GABAergic function. While prolonged exposure
and withdrawal may accentuate anxiety, a brief exposure to neurosteroids during stress may serve to dampen
anxiety and the stress response. Alternatively, as discussed by Backstrom and colleagues in Chapter 13,
ALLO may exert a bimodal effect on anxiety/mood/
irritability/aggression, with lower doses that result in
blood levels similar to those seen during the luteal
phase, leading to negative affect in vulnerable individuals, while higher doses, similar to those seen in late
pregnancy, are noted to improve mood.

Why consider the relationship between
glutamate and GABA?
These profound, and often opposing effects of estrogen
and progesterone highlight the importance of ‘striking
a balance’ in the neuroendocrine milieu in order to
maintain cognitive and neurobehavioral health.
Although this is likely to be true with multiple neurotransmitter systems, the intimate link between the
glutamatergic and GABAergic systems with respect to
their synthesis and actions in the CNS is unique and
underscores their critical role in balancing neuronal
excitation and inhibition. Furthermore, glutamate and

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GABA constitute more than 90% of cortical neurons in
the adult mammalian brain39 and are highly sensitive to
sex hormones and neurosteroids.
Before reviewing the literature demonstrating altered
GABAergic function in women with PMS/PMDD, it is
important to consider the synthetic relationship
between glutamate and GABA. In addition, glial cells,
which were once simply thought to support neuronal
function, are also sensitive to sex hormones and play a
critical role in glutamate and GABA uptake from the
synapse. Figure 11.1 depicts what is considered to be
the ‘tripartite synapse’, which is composed of a presynaptic glutmatergic neuron, a postsynaptic neuron
(in this case a GABAergic neuron), with a glial cell in
close proximity to the synaptic cleft (reviewed by
Hyder et al40). Glutamate is released from the presynaptic neuron and taken into the GABAergic neuron; it
is transported and converted to GABA by glutamic acid
decarboxylase (GAD). The astrocyte rapidly removes
glutamate from the cleft via glutamate transporters,
converts glutamate, to glutamine, and then releases
glutamine, which can be recycled to supply glutamate
for further neuronal release.
Glutamatergic stimulation of brain glucose utilization
(reviewed by Sibson41), and thus neuronal and glial
energetics, is yet another means by which sex hormones
may alter brain function and behavior at a fundamental

Glutamatergic
neuron

glut

Glial cell
glut

glut
gln

glut
GABAergic
neuron

GAD

GABA

Figure 11.1 Normal glutamate–GABA–glutamine
cycling. Glutamate (glut) is released from
glutamatergic neurons. A portion of glut is taken up
by glial cells and converted to glutamine (gln), which
can then be released and taken up by glutamatergic
neurons and converted back to glut. Alternatively,
gln can be taken up by ␥-aminobutyric acid (GABA)
neurons, converted to glutamate and then to GABA
by glutamic acid decarboxylase (GAD).

level. One of the ways in which estrogen is thought to
mediate its neuroprotective effects is by enhancing astrocyte uptake of glutamate from the synaptic cleft.6,42
Glutamate uptake then triggers a cascade of intracellular
events, which leads to vasodilatation.43 Through this
mechanism astrocytes provide the critical link between
neuronal activity, glucose utilization, and the functional
hyperemia underlying the BOLD effect measured in
fMRI studies (reviewed by Hyder et al40). Furthermore,
postmenopausal women have relatively lower CBF
as measured using SPECT, than premenopausal
women.44,45 Postmenopausal ET improves CBF in postmenopausal women, even those with previous CBF
impairments due to cerebral vascular disease.44 Whether
this effect of estrogen is solely mediated by estrogen’s
direct impact on vascular tone or whether estrogen
modulation of astrocytic glutamate uptake is a contributing factor is not clear. However, a PET study suggests that estrogen is responsible for the relatively higher
cerebral glucose utilization in women than in men.46

Clinical evidence
The temporal association between the symptoms of
PMS/PMDD and postovulatory increases and decreases
in progesterone and its neurosteroid derivatives has
prompted much investigation. While findings from
studies focusing on peripheral measures of estradiol,
progesterone, ALLO, and PREG have been disappointingly inconsistent, taken as a whole, they suggest that
peripheral abnormalities in steroid levels and/or ratios
are unlikely to be a major factor in the pathogenesis of
PMS/PMDD. Instead, it is generally held that negative
affective states occurring during the premenstruum,
pregnancy/postpartum, and perimenopause are due to
an anomalous interaction between steroids and their
CNS targets. Alternatively, altered brain production of
neurosteroids has not been ruled out.
In an effort to glean information regarding the role
of GABAergic function in PMS/PMDD, Backstrom,
Sundstrom, and colleagues from Sweden have conducted a number of seminal studies in which women
with PMS/PMDD and healthy controls have been given
a series of GABAA receptor agonists during the follicular and luteal phases of the menstrual cycle (described
in Chapter 13 and reviewed in detail by Sundstrom
Poromaa et al47). Using saccadic eye velocity (SEV) as
an assay for GABAA receptor agonist activity, they
found that healthy women are more sensitive to these
agents during the mid-luteal phase when endogenous
progesterone, estrogen, and neurosteroid levels are
elevated than in the hypogonadal follicular phase.
However, women with PMS/PMDD did not show this
luteal phase sensitivity, a finding that is consistent with

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PATHOPHYSIOLOGY II: NEUROIMAGING, GABA, AND THE MENSTRUAL CYCLE 105

the preclinical data indicating that chronic exposure to
neurosteroids can lead to reduced benzodiazepine sensitivity. Although it is unclear why this did not happen
to healthy women, as one would presume that animal
models using healthy organisms would reflect what is
meant to be occurring in healthy humans, it does
provide evidence in the human laboratory that altered
GABAergic function contributes to the pathogenesis of
PMS/PMDD. Moreover, selective serotonin reuptake
inhibitors (SSRIs), which are preferentially efficacious
in the treatment of PMS/PMDD (reviewed by Wyatt
et al48), are known to enhance brain and cerebrospinal
fluid (CSF) levels of ALLO in rodents and humans,
respectively.49,50 When administered in concert with
fluoxetine, ALLO has been shown to enhance the antidepressant effects of the SSRI in the forced swim test,
an animal model for depression.51 That SSRIs are effective with luteal phase48 and possibly symptom-onset
treatment52 suggests that blockade of serotonin reuptake may not be critical for the clinical efficacy of these
agents and opens the possibility that SSRI modulation
of ALLO, and thus GABA, may be imperative.
Research from other laboratories using a diverse array
of investigative techniques has also implicated GABAergic dysregulation in PMDD. Using transcranial magnetic stimulation (TMS), Smith and co-investigators53
sought to examine the balance of neuronal excitation
and inhibition in the motor cortex under different hormonal states. In healthy controls, the late follicular
phase (elevated estradiol) was characterized by enhanced
facilitation, which is thought to reflect an increase in
glutamatergic function and overall cortical excitation.
In the luteal phase, the pattern was more consistent
with increased paired-pulse inhibition, which isn’t surprising given this is the effect seen with benzodiazepine
or barbiturate administration (reviewed by Ziemann
et al54). In a later study, women with PMDD showed a
follicular to luteal phase increase in facilitation55
instead of the increase in inhibition seen in healthy controls. These findings provide further clinical evidence
that the balance between cortical excitation and inhibition is altered in the luteal phase of women with
PMDD. Whether this is due to an enhancement of glutamatergic function or a reduction in GABAergic function is not known. However, either could tip the scale
towards excessive excitation during the luteal phase.
Coming full circle to the role of neuroimaging as a
tool to study PMS/PMDD, we utilized 1H-MRS to
investigate how occipital cortex GABA concentrations
change across the menstrual cycle in women with
PMDD and healthy controls.17 Although luteal phase
levels did not differ between groups, women with
PMDD appear to have a deficiency in cortical GABA in
the non-symptomatic follicular phase. In healthy controls,

GABA levels were highest during the follicular phase
and decreased as plasma estradiol, progesterone, and
ALLO increased in the luteal phase. In women with
PMDD, however, GABA levels increased with neuroactive steroid levels. In addition, there was a significant
correlation between GABA and ALLO in healthy controls, but not in women with PMDD, suggesting an
abnormal relationship between GABA and ALLO in
these women.17 These findings are consistent with
those of Sundstrom and Backstrom discussed previously: namely, that women with PMDD have an atypical GABAergic response to endogenous or exogenous
GABAA receptor agonist exposure.
Because nicotine is known to interact with amino
acid neurotransmitter systems and women smokers
appear to be at heightened risk of negative affect during
smoking cessation, we investigated the effects of shortterm smoking abstinence on occipital cortex GABA
concentrations across the menstrual cycle in healthy
female smokers.56 Although there were no significant
effects of 48 hours of abstinence, female smokers
showed a lack of cyclicity in baseline cortical GABA
level compared with healthy non-smokers, which
resulted in decreased follicular phase GABA levels.
These findings suggest that substances such as nicotine,
which chronically alter GABA or glutamate, are likely
to alter the normal neuroendocrine milieu in women.
Finally, a recent pilot study demonstrated that, unlike
certain subtypes of major depressive disorder,57 cortical
GABA levels are not reduced in postpartum depressed
women compared with postpartum healthy controls.58
However, both groups had lower cortical GABA levels
than follicular phase controls despite both groups being
in a relatively hypogonadal state. While preliminary,
these data suggest that reductions in cortical GABA
concentration may be permissive but not causal for
postpartum depression.
Although 1H-MRS is a non-invasive way of measuring
brain GABA concentrations, our work to date has been
restricted to the occipital cortex, which is not typically
implicated in the pathogenesis of affective disorders.
One cannot rule out the possibility that GABAergic and
glutamatergic systems in other brain regions will experience different effects of neurosteroids and their interactions with other neurotransmitter systems. However,
as in much of the cortex, GABA and glutamate neurons
in the occipital cortex are a target for neuroactive
steroids. In addition, GABAA receptor regulation in the
occipital cortex has been associated with other changes
in limbic and cortical regions.59
Although 1H-MRS provides the means to measure
amino acid neurotransmitters in vivo, it is limited in its
ability to infer the functional significance of menstrual
cycle alterations in cortical GABA concentrations. In the

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106 THE PREMENSTRUAL SYNDROMES

future, 1H-MRS studies could examine the effects of
acute and/or chronic administration of GABAA receptor agonists with affinity for the different receptor subunits. Unfortunately, there is not yet a pharmacological
probe specific for the ␣4 receptor subunit. Nevertheless,
menstrual cycle phase and/or diagnostic specific
changes in GABA concentrations with various agonists
could provide further information regarding the functional integrity of this neurotransmitter system.
In addition, more advanced MRS techniques such as
13-carbon MRS (13C-MRS) would allow for a dynamic
assessment of glutamate–glutamine and GABA–glutamine
cycling under different hormonal conditions. These
studies would enable investigators to examine the impact
of neuroactive steroids on GABA and glutamate synthesis as well as brain energy consumption.

SUMMARY
We have reviewed in this chapter the extant data
regarding PET, SPECT, fMRI, and 1H-MRS studies
across the menstrual cycle. Taken as a group, they
provide considerable evidence that hormonal changes
alter brain function and chemistry in humans in a
manner that is relatively consistent with that seen in
rodents and non-human primates. While the majority
of neuroimaging studies focus on the role of estrogen in
cognitive processes, functional studies are now addressing the impact of sex steroid/menstrual cycle phase on
the neuronal processing of affective tasks. As each of
these fMRI studies examined women at slightly different
points in the menstrual cycle and two of the three did
not confirm menstrual cycle phase with estrogen or
progesterone levels, it is somewhat difficult to compare
results. However, altogether, they seem to suggest that
menstrual cycle phase and/or estrogen alters response
to emotionally laden stimuli; whether this hormonal
effect is specific to positive or negative stimuli is not
yet clear.
Relatively new neuroimaging techniques such a
1H-MRS and 13C-MRS enable investigation of the
impact of ovarian hormones and neurosteroids on
amino acid neurotransmitter concentration and flux,
respectively. Present data provide additional, more
direct evidence that GABAergic dysregulation contributes to the pathogenesis of PMDD. Future studies
using MRS techniques should be designed to address
functional efficacy of the GABAergic system. Finally,
all neuroimaging studies should take into consideration
the potential for the menstrual cycle to alter outcomes
of interest. If the impact of sex steroids is not the focus
of a particular neuroimaging paradigm, then studying
women during the early to mid-follicular phase (days

1–8) will reduce the likelihood that hormonal variability will contribute significantly to the finding. When the
impact of menstrual cycle and/or hormones is the
outcome of interest, it is critical that hormone levels are
obtained to confirm endocrine status on each test day.

INTRODUCTION
The importance of PMS/PMDD has been summarized
in previous chapters and we will begin by briefly summarizing this. Premenstrual syndrome (PMS) is a condition of recurrent physical and psychological symptoms
that occurs in a cyclic fashion during the 1- to 2-week
period preceding a woman’s menstrual period. Most
surveys have found that as many as 85% of menstruating women report one or more mild premenstrual
symptoms. Severe symptoms that meet the criteria for
PMS, however, are much less common, with only 10%
of women reporting significant impairment in their
lifestyles.1 Premenstrual dysphoric disorder (PMDD), a
variant of PMS that entails more severe psychological
symptoms and impairment of functioning, occurs in
2–9% of women of reproductive age.2 This chapter will
focus on hormonal treatments that have been used in
both PMS and PMDD, since only recent studies have
examined the latter.
Although the etiology of PMDD is incompletely
understood, the leading hormonal theory is related to
fluctuating sex steroid levels. Although there is a temporal relationship between symptoms of PMDD, female
sex hormones, and phases of the menstrual cycle, women
with PMDD show no consistent diagnosis-related differences in basal levels of ovarian hormones.3 We have
already seen that the likely etiology of PMS/ PMDD is
the effect of postovulatory progesterone in sensitive
women. This progesterone sensitivity is probably due
to abnormal neurotransmitter function. Thus, in general terms, treatment can be achieved by means of
correction of the neurotransmitter status, for example,
by use of selective serotonin reuptake inhibitors (SSRIs)
or by suppression of ovulation. Chapter 14 deals with
the concept of treatment by ovarian suppression. In
this chapter we outline the role of hormone therapy.

There is inevitably some overlap and differences of
opinion.
Suppression of ovarian function with pharmacotherapy4–6 or through surgical menopause7,8 eliminates the
symptoms of PMDD. Moreover, symptoms are eliminated during pregnancy and are absent during nonovulatory cycles and after menopause.9 The most likely
explanation is that women with PMDD are in some
way vulnerable to the normal physiological changes
associated with the menstrual cycle.3 This hypothesis
was supported in one study where women with PMDD
developed depressed mood in response to challenge
with physiological levels of estrogen and progesterone
compared with controls.10
Androgens have also been suggested in the etiology
of PMS/PMDD because of the prominence of irritability in the symptom profile. Elevated testosterone levels
have been reported in women with severe premenstrual
irritability,11 and a positive correlation has been observed between free testosterone concentrations and irritability.12 Moreover, some success has been reported in
treating PMDD with androgen antagonists.11 There are
other studies where complex interactions with serotonin and even lower testosterone levels have been
shown, leading to the use of testosterone for treatment.
Finally, metabolites of progesterone, allopregnanolone and pregnanolone, may be decreased in women
with PMDD. These metabolites may have a positive
effect on the central nervous system similar to that of
GABA (␥-aminobutyric acid), and deficiencies may give
rise to premenstrual symptoms.13

steroids with a stable endogenous hormonal environment. For this reason, combined OCPs have been used
to treat premenstrual symptoms.14 Unfortunately, unless
given continuously, the OCPs introduce a new exogenous
hormone cyclicity that results in a confusing picture
when treatment studies are analyzed.
The major trend in the formulation of OCs over the
last 40 years has been a reduction in the doses of both
the estrogen and the progestin components, and, more
recently, chemical alterations of the progestins to provide
less androgenic compounds.9 Estradiol (ethinyl estradiol) doses have decreased from 100 ␮g to 20–30 ␮g.
The dose of the progestin component has also decreased. All but one currently prescribed OC still contains a
progestin derived from 19-nortestosterone. Table 12.1
summarizes the pharmacological profile of progesterone,
19-nortestosterone, and a new progestin drospirenone
derived from spironolactone.15
The palliative effect of OCPs, particularly for physical premenstrual symptoms, has been suggested by previous epidemiological and non-placebo-controlled
research.14,16–18 There have been three randomized,
placebo-controlled trials investigating OCPs in treating
premenstrual symptoms, one evaluating PMS19 and
two evaluating PMDD.20,21
In the first randomized trial, a triphasic formulation
reduced physical symptoms but not mood alterations.19
The study enrolled 82 women with PMS, and the active
treatment was a triphasic OCP (ethinyl estradiol 35 ␮g
⫹ norethindrone 0.5 mg days 1–7 and 17–21 and 1.0 mg
days 8–16).19 Differences between the OCP and placebo were minimal, although mood worsened in the

active-treatment group during the hormone-free, postmenstrual period.
The other two trials evaluated a new progestin,
drospirenone, which possesses spironolactone-like
antimineralocorticoid and antiandrogenic activity.15
Previous studies of the diuretic spironolactone in PMS
have demonstrated its efficacy in relieving the physical
symptoms (bloating, breast tenderness) and the psychological symptoms (mood change, irritability) of this
condition.22–24 The antiandrogenic activity of drospirenone may improve premenstrual irritability and
acne,25 which may be due to elevated plasma testosterone in women with PMS.26,27
Freeman et al compared placebo to an OCP with
drospirenone 3 mg and ethinyl estradiol 30 ␮g in a
21/7 platform to 82 women who met PMDD criteria.20
The active treatment was associated with significantly
greater improvement in appetite, acne, and food cravings, but there were no differences between groups in
mood symptoms. The lack of between-group differences in mood symptoms may have been due to the
modest sample size in the setting of a considerable
placebo response rate (43%).
The more positive findings in the Freeman20 compared with the Graham19 study may be due to the use of
a progestin that has antimineralocorticoid and antiandrogenic properties not observed in the progestins derived
from 19-nortestosterone, such as norethindrone.15
Recently, a controlled study conducted by Yonkers
et al21 showed that the drospirenone-containing OCP
formulation administered for 24 of 28 days in a cycle
ameliorated symptoms associated with PMDD compared

with placebo in 450 women.21 Mood symptoms (e.g.
depression, anxiety, mood swings, irritability), behavioral symptoms (difficulty concentrating, sleep disturbance), and physical symptoms (e.g. fatigue, increased
appetite, breast tenderness, headaches) were all significantly reduced with the OCP compared with placebo.
It is particularly significant that active treatment was
associated with a 49% reduction in premenstrual
depression, as OCPs have been thought by some to
worsen or cause symptoms of depression.28,29
The differences in estrogen dose and shortened drugfree interval between the Yonkers21 and the Freeman20
studies may explain the more favorable results in the
former study. The Freeman study20 used a higher dose
of estradiol than the Yonkers study21 (e.g. 30 ␮g rather
than 20 ␮g), and the active drug was given for 21
rather than 24 days in a 28-day cycle.
In addition to their effect on premenstrual symptoms, there are numerous health advantages afforded
by intake of OCPs. They provide effective, reversible
contraception but also have other known benefits,
including prevention of bone loss, decreased risks for

ovarian and endometrial cancer, anemia, abnormal
uterine bleeding, uterine myomata, endometriosis,
pelvic inflammatory disease, as well as complications
of unplanned pregnancy, such as ectopic pregnancy and
molar gestation.9,18 The most bothersome physical side
effects of OCPs are bloating and breast tenderness, and
these symptoms are, at least in part, attributable to
water retention, probably related to their estrogenic
component.9,18
Currently, the evidence suggests that OCPs should be
considered if premenstrual symptoms are primarily
physical, and the newer OCPs containing antiandrogenic
progestins may be effective in treating mood symptoms
as well. More controlled studies are needed to confirm
the efficacy of continuous vs cyclical oral contraceptives
in ameliorating premenstrual symptoms.30 The newer
OCPs with lower-dose estrogen and drospirenone may
have a unique role in women who both desire contraception and suffer from symptoms of PMDD.
Table 12.2 lists the evidence supporting the efficacy
and safety of OCPs as well as the other hormonal
therapies to be discussed in this chapter.

Table 12.2 Evidence-based guidelines on the use of hormonal treatments in PMS/PMDD
Treatment

ESTRADIOL
A high dosage of estradiol in the form of transdermal
estradiol patches or subcutaneous implants has been
given to suppress ovulation in controlled studies.31–35
To hinder endometrial hyperplasia, cyclical progestogens are given to ensure a regular withdrawal bleed.
Both routes of administering estradiol have shown positive effects for treating mental and physical symptoms
in two non-controlled studies.
A randomized, prospective trial comparing estradiol
patches in dosages of 100 and 200 ␮g twice weekly,
combined with cyclical progestogens, showed no difference in the effectiveness of these two dosages. However, a greater dropout rate and a greater incidence of
adverse effects attributed to estrogen was noted in the
higher-dosage group.34
A long-term follow-up study of 50 patients who had
used estradiol implants for PMS for a mean of 5.6 years
(range 2–8 years) was conducted.35 There was a continued beneficial response to treatment for all symptoms, varying from 74% for bloating to 96% for
depression. Cyclical progestogenic symptoms occurred
in 58% of patients. These were partially relieved by
alteration in dose, type, and duration of progestogen
treatment, but in seven patients the symptoms remained
severe. Attempts to reduce the dose of progestogen led to
cystic hyperplasia in four patients. There were no complications from venous thrombosis, pulmonary embolus,
or breast disease of atypical endometrial hyperplasia.
Based on insufficient data on efficacy and potentially
significant adverse events, high-dose estrogen is not
recommended for treating PMS/PMDD.

PROGESTERONE
The rationale for the use of progesterone and progestogens in the management of premenstrual symptoms was
based on the premise that progesterone deficiency is the
cause.36 Historically, natural progesterone has been one
of the most commonly employed therapies in women
with PMS, but careful scientific scrutiny has not supported an overall benefit of this hormone when compared with placebo, whether administered as a vaginal
suppository37 or as oral micronized progesterone.13
Recently, a meta-analysis was conducted and included only those controlled trials that required a diagnosis
of PMS.9 Ten trials of progesterone therapy (531 women)
and four trials of progestogen therapy (378 women)
met criteria. None of the eight trials of progesterone
suppositories were shown to have a positive effect.
Micronized oral progesterone was found to have some
benefit in a study of 23 patients38 but a larger study of

106 patients found no difference between active treatment and placebo. There have been no controlled
studies on topical progesterone cream, despite the fact
that it has been popularized throughout the media and
the Internet.
Four of 15 progestogen studies were included in the
meta-analysis. Of those studies, two used dydrogesterone, one used norethisterone, and one used medroxyprogesterone. Medroxyprogesterone was found to be
significantly more effective than placebo in improving
both psychological symptoms and breast symptoms in
19 patients,39 whereas norethisterone showed significantly greater improvement than placebo in treating
breast symptoms only in 16 women.39 However, didrogesterone was found to be no more effective than
placebo in one study of 24 women40 and in a larger
study of 260 patients.41 The low numbers of participants
did not permit a comparative analysis of individual
progestogens to be undertaken. The author concluded
from the meta-analysis that exogenous administration
of either progestogens or progesterone does not improve
symptoms.

DANAZOL
Danazol, a progestogen with some androgen properties, given for the treatment of endometriosis, has also
been used in the treatment of PMS. The dosages used in
PMS treatment – 100 mg twice a day or 200 mg once a
day – are lower than the dosages used for endometriosis. At these dosages, ovulation inhibition occurs in the
majority of cases.18 Five placebo-controlled, doubleblind studies and one open-label study evaluated the
efficacy of danazol 200 mg/day.42–46 In each study,
danazol had a beneficial effect on PMS symptoms compared with placebo in cycles where anovulaton was
obtained, despite the relatively small sample sizes of the
studies. Danazol is known to have androgenic adverse
effects on lipids and to cause acne, vocal changes, and
negative mood at dosages used for endometriosis.
However, these symptoms were not observed with the
dosages used in the six aforementioned studies. Despite
this, the study withdrawal rates were higher in these
studies (32.5%) than those seen in other PMS studies
(11.5%).44 Although studies have consistently shown
danazol to effectively treat premenstrual symptoms, its
side effect profile suggests its use only in patients who
have failed more conservative treatments. Attempts to
reduce side effects have been made by administering
danazol in the luteal phase only. Whilst Sarno has
demonstrated a beneficial effect on the general symptoms of PMS as well as for cyclical mastalgia, when
patients are stratified, only breast-related symptoms

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HORMONAL THERAPIES OVERVIEW 113

are improved. Luteal phase danazol is a very effective
treatment for breast symptoms and with virtual elimination of symptomatic side effects.

GONADOTROPIN-RELEASING
HORMONE AGONISTS
Gonadotropin-releasing hormone (GnRH) agonists are
an example of a group of drugs that suppress ovarian
function, which is believed to be the trigger for PMDD.47
GnRH agonists down-regulate the gonadotropin receptors in the pituitary gland to create a hypogonadotropic
state whereby ovarian function is suppressed to menopausal levels and amenorrhea is induced.47 Due to the
low serum estradiol concentrations induced by GnRH
agonists, side effects are common and, because of
potential bone demineralization,48 treatment with these
compounds is usually restricted to 6 months.49 In order
to lengthen the period that GnRH agonists can be
administered, several studies have used concomitant ‘addback’ hormone replacement therapy. GnRH agonists are
not frequently prescribed in primary care because of
cost and side effects.
Recently, a meta-analysis of published randomized
placebo-controlled trials was conducted to evaluate the
efficacy of GnRH agonists with and without ‘add-back’
therapy in women with a diagnosis of PMS.47 Five
trials without add-back therapy (71 women on active
treatment) met inclusion criteria. The equivalent odds
ratio (OR) was 8.66 in favor of GnRH agonists. GnRH
agonists were more efficacious for physical than behavioral symptoms, although the difference was not statistically significant. Women were three times more likely
to experience side effects on treatment compared with
placebo, which included hot flashes, aches, night sweats,
and nausea. Of the five included trials, three used depot
GnRH agonists,4,6,50 one used daily injection,51 and
another gave GnRH agonists as a nasal spray.52
However, the efficacy of individual GnRH types and
routes of administration could not be assessed in the
meta-analysis, owing to the small number of trials and
participants.
Three randomized controlled trials (64 patients in
total) compared the efficacy of add-back therapy
and GnRH agonists ⫹ placebo in the management
of PMS.5,50,53 There was no significant reduction in
effectiveness of GnRH agonists with the addition of
add-back therapy. These finding were confirmed in a
subsequent study of leuprolide acetate with and
without add-back.54 However, women were more likely
to drop out of the trial while on add-back therapy.
Future studies on GnRH agonists in PMDD should
include those which assess the safety of long-term

DIETARY SUPPLEMENTATION
Some dietary supplements are thought to interact with
steroid activity and are therefore considered here.

Chasteberry
Chasteberry, the fruit of the chaste tree (Vitex agnuscastus), is commonly used for treating premenstrual
symptoms. Active constituents in chasteberries are the
essential oils, iridoid glycosides, and the flavonoids.55
The mechanism of action is unclear, but it may involve
decreasing estrogen, and increasing progesterone, prolactin, and dopamine levels.56 A 3-month, randomized
double-blind placebo-controlled study of 217 PMS/
PMDD subjects found chasteberry (600 mg three times
daily) only alleviated restlessness.57 Another study
showed that chasteberry and vitamin B6 had similar
reductions in PMS scores (77% and 66%, respectively).58 In general, the data show conflicting results
but appear promising.

Black cohosh
The majority of studies looking at black cohosh
(Cimicifuga racemosa) have been in the treatment of
menopausal symptoms. The mechanism of action
remains somewhat unclear, but may involve suppressing luteinizing hormone secretion.56 A number of
studies using Remifemin, a proprietary extract of black
cohosh, show efficacy in treating menopausal symptoms (hot flashes, profuse sweating, sleep disturbance,
and depressive moods).59 Because these symptoms often
present in women with PMDD, many clinicians have
recommended the use of black cohosh in this population. Further clinical studies are needed to determine
the efficacy of black cohosh in PMDD. The recommended dose is 40–80 mg of a standardized extract
twice daily, providing 4–8 mg of triterpine glycosides.59

CONCLUSIONS
The ideal choice of a hormonal treatment in PMS/ PMDD
would be based on randomized, placebo-controlled

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114 THE PREMENSTRUAL SYNDROMES

trials consistently demonstrating efficacy in the treatment of emotional and physical symptoms with
minimal side effects. Figure 12.1 provides an algorithm
for hormonal treatments for PMS/PMDD. Oral contraceptives are the agents of first choice because they most
closely approximately this goal. They do, however,
introduce a new progestogen cyclicity that may negate
its effect. Their efficacy in treating physical premenstrual
symptoms has been demonstrated in controlled trials
and they produce minimal to mild side effects. Moreover, they provide additional benefits such as contraception, control of abnormal uterine bleeding, and
management of other pelvic conditions. Contraceptives
containing drospirenone show potential. Recent data
suggest that low-dose estrogen and antiandrogenic/
antimineralocorticoid progestins, such as drospirenone,

Figure 12.1 Algorithm for hormonal treatment of
PMS/PMDD. OCPs = oral contraceptive pills; GnRH
agonists = gonadotropin-releasing hormone agonists.
Avoid estradiol patches and implants due to
insufficient evidence of efficacy and potentially
significant side effects from high-dose estrogen. Avoid
progesterone suppositories and micronized tablets
because of lack of efficacy. Avoid ovariectomy because
of insufficient efficacy data and major side effects.
Chasteberry and black cohosh may be suggested, but
presently there is insufficient data to suggest their
efficacy and/or potential side effects.

may also ameliorate emotional premenstrual symptoms, but further study is needed.
A recent meta-analysis of GnRH agonists demonstrated their efficacy in treating symptoms of PMS/
PMDD. Their side effect profile and cost precludes
long-term use, although there is some evidence to
suggest that side effects can be reduced by add-back
therapy with no detrimental effect on efficacy. Shortterm therapy with GnRH agonists ⫹ add-back therapy
is recommended when other treatment has failed and
the woman demonstrates significant functional impairment from physical symptoms.
Like GnRH agonists, danazol has consistently shown
efficacy in treating physical symptoms of PMS/PMDD
in controlled studies. However, its practical use is
limited by the need for concurrent administration of a
reliable contraceptive method, weight gain, mood
changes, acne, and possible virilization of the fetus.
Thus, danazol is a suggested treatment for PMS/PMDD
only when OCPs and GnRH agonists have failed, and
premenstrual symptoms are significantly impairing
daily functioning. It is a useful drug used in the luteal
phase only in treating breast symptoms, and this is
associated with minimal side effects.
High-dose estradiol has been investigated in a
number of trials. No incidents of venous thrombosis,
pulmonary embolus, or atypical endometrial hyperplasia occurred, but risks remain high. Estradiol patches
and implants are not recommended for treating
PMS/PMDD by the authors of this chapter, but there
are differing views based on the same evidence (see
Chapter 14).
Historically, natural progesterone has been one of
the most commonly employed therapies in women with
PMS/PMDD, but controlled trials have consistently
shown no benefit of this hormone when compared with
placebo, whether administered as a vaginal suppository
or as oral micronized progesterone. Therefore, it is not
recommended as treatment.
Data regarding use of dietary supplements which
affect endocrine function is scant and conflicting.
Clinical experience has shown no significant side effects
of either chasteberry or cohosh, and there is anecdotal
evidence to suggest a benefit.

13
The role of progesterone and GABA in
PMS/PMDD
Torbjörn Bäckström, Lotta Andréen, Inger Björn, Inga-Maj Johansson, and Magnus Löfgren

TEMPORAL SYMPTOM – HORMONE
RELATION
The relationship between the luteal phase of the menstrual cycle and symptom development in premenstrual
dysphoric disorder/premenstrual syndrome (PMDD/
PMS) is self-evident. Symptoms starts after ovulation and
then increase in parallel with the rise in serum progesterone during the luteal phase. The symptom severity
reaches a peak during the last five premenstrual days or
the first day of menstruation. Thereafter, the symptoms
decline and disappear 3–4 days after the onset of menstrual bleeding. During the postmenstrual phase there
is a period of well-being, closely following estrogen
production, to the estradiol peak. This suggests that
there is a symptom-provoking factor produced by the
corpus luteum of the ovary.1 This is further supported
by the fact that in anovulatory cycles, spontaneous or
induced, when a corpus luteum is not formed, no
symptom cyclicity occurs.2–4

NATURE OF THE SYMPTOM-INDUCING
FACTOR PRODUCED BY THE CORPUS
LUTEUM OF THE OVARY
Further evidence that progesterone and progestogens
induce negative mood symptoms similar to those in
PMDD/PMS is seen in postmenopausal women receiving estrogen/progesterone hormone therapy.5–7 As discussed above, there are strong indications that steroids
from the corpus luteum are the symptom-provoking
factor in the central nervous system (CNS). But the
classical hormonal receptor for progesterone seems not
to be involved in the pathophysiology of PMS/PMDD;
treatment with the progesterone receptor antagonist

mifepristone (RU-486) fails to reduce the physical or
behavioral manifestations of PMS.8

THE DIRECT EFFECTS OF NEUROACTIVE
PROGESTERONE METABOLITES ON THE
GABA-A RECEPTOR
To understand progesterone-induced adverse mood
effects, it is important to note that progesterone is to
high degree metabolized to allopregnanolone (3␣-OH5␣-pregnan-20-one) and pregnanolone (3␣-OH-5␤pregnan-20-one), both of which act as agonists on the
␥-aminobutyric acid A (GABAA) receptor complex in
the brain.9 The GABA transmitter system is the major
inhibitory system in the CNS. When GABA binds to the
GABAA receptor, the influx of chloride ions increases,
hyperpolarizing the postsynaptic membrane and making
the postsynaptic cell less prone to excitation. Allopregnanolone is a GABAA receptor positive modulator
and enhances the effect of GABA on the receptor. The
behavioral and pharmacological characteristics are
similar to ethanol, barbiturates, and benzodiazepines.
Neurosteroids, benzodiazepines, barbiturates, alcohol,
and most anesthetic agents bind to the GABAA receptor
and increase the GABA-induced chloride ion influx by
interacting with allosteric binding sites.10,11

GABAA receptor agonistic effects such as sedation/
anesthesia,12,13 anti epileptic effects,14 anxiolytic effects15
of high doses of allopregnanolone and pregnanolone.
Studies have also reported the negative effects of allopregnanolone, which has been shown to increase irritability/aggression16 and inhibit learning.17 Treatment
with progesterone in a rat model of PMDD induces
anxiety, related to an increased 4 subunit of the GABAA
receptor in hippocampus, which in turn is attributed to
an allopregnanolone effect.18 Similar results, with a
place aversion as a measure of anxiety in rats, were
noted with a low dosage of allopregnanolone.19
Besides the neuroactive progesterone metabolites,
benzodiazepines, barbiturates, and alcohol also act as
positive modulators of the GABAA receptor. Recent
reports from human and animal studies indicate that in
certain individuals all GABAA receptor agonists can
induce negative symptoms with anxiety and irritability/
aggression. Strong irritability/aggression is induced in
3–6% of individuals; moderate symptoms are induced in
20–30%. Interestingly, the frequency parallels the
3–8% prevalence of PMDD among women in reproductive age and the 25–35% prevalence of milder
symptoms, as in PMS.20–22

THE GABA ACTIVE AGONIST PARADOX
The GABAA receptor agonists are known to be anxiolytic, sedative, and antiepileptic. Why an increase in
allopregnanolone is related to development of negative
mood is puzzling. It appears that benzodiazepines,
barbiturates, alcohol, and allopregnanolone possess
bimodal action on mood symptoms. In both animals
and humans, GABAA receptor agonists in high doses
are anxiolytic, antiaggressive, sedative/anesthetic, and
antiepileptic.23,24 However, in low concentrations or
doses, severe adverse emotional reactions are induced
in a subset of individuals (2–3%) and moderate reactions in up to 20%. This paradoxical effect is induced
by allopregnanolone,16,19 benzodiazepines,25,26 barbiturates,20,27 and ethanol.16,28 The symptoms induced
by these GABAA receptor active drugs include depressed
mood, irritability, aggression, and other typical symptoms of PMS/PMDD. A similar bimodal effect has also
been noted for different doses of medroxyprogesterone
(MPA) and natural progesterone in postmenopausal
women taking hormone replacement therapy (HRT).
These women feel worse on a lower dosage of MPA
or progesterone than they do on higher doses or
placebo.29,30
Thus, allopregnanolone seems to have a bimodal
effect on mood with an inverted U-shaped relationship
between concentration and effect. In postmenopausal

women receiving vaginal or oral progesterone, a biphasic
relation between the negative mood symptoms and the
allopregnanolone concentrations in blood is noted.
Negative mood increases with the rise in serum concentration of allopregnanolone up to a maximum, but then
further increase in allopregnanolone concentration is
associated with a decrease in the severity.5,31 The increase
in negative mood occurs at serum concentrations within
the range seen during the luteal phase. With concentrations
seen during late pregnancy, the symptoms decrease.32,33
In late pregnancy when allopregnanolone concentrations
are at their highest, PMDD patients often feel better. A
similar inverted U-shaped relationship between allopregnanolone dose and irritability/aggression has also
been noted in rats.16
Benzodiazepines also induce paradoxical reactions in
certain individuals, with irritability, aggression, depression, confusion, violent behavior, and loss of impulse
control compared with placebo.25,26 Weinbroum et al
reported a 10.2% incidence of paradoxical events to
midazolam in patients who underwent surgery during
a 3-month period and showed that the treatment
with flumazenil (a benzodiazepine receptor antagonist)
effectively reversed midazolam-induced paradoxical
behavior.22 Several reports from animal studies on
benzodiazepine-heightened aggression show similar
antagonistic effects of benzodiazepine antagonists, as
seen in humans.34

ROLE OF ESTRADIOL IN
PROGESTERONE-INDUCED
MOOD SYMPTOMS
Estradiol concentration is also of importance in relation
to the mood-inducing effect of progesterone. Higher
estradiol doses in HRT during the progestogen period
gave more severe symptoms compared with lower estradiol dosage in the same women but only during the
period when the progestogen was given. During the
period of unopposed estrogen, no difference in mood
severity was noted in relation to the estrogen dose.35
Similar results were seen in women with PMS/PMDD
(but not controls) with, interrupted ovarian function
where both estradiol and progesterone induced symptoms.36 Increased plasma levels of estradiol and progesterone during the luteal phase in patients with PMS are
related to more severe symptoms compared to cycles in
the same individuals with lower levels.37 Moreover,
estradiol treatment during the luteal phase induced
more negative symptoms than placebo in PMS/PMDD
patients.38 Estradiol and progesterone acting together
seem to induce differing responses in the CNS than
when they act separately.

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SENSITIVITY IN THE GABA SYSTEM IN
PMDD/PMS PATIENTS
It appears that a subset of individuals are very sensitive
to low doses or concentrations of allopregnanolone
and have severe adverse emotional reactions when provoked. There is evidence that steroid sensitivity in the
brain differs between PMS/PMDD patients and controls. Negative effects of oral contraceptives on mood
were found mainly in women with PMS/PMDD.39
Add-back estradiol or progesterone, in women with
PMS/PMDD and inhibited ovarian hormone production, gave rise to recurrence of symptoms. This did not
happen either in normal women or in PMS/PMDD
women during placebo treatment.36 Postmenopausal
women with a history of PMS/PMDD respond with
more negative symptoms on progestogens than women
without a PMS/PMDD history.6 In PMS/PMDD
patients but not controls, the sedative response to intravenous pregnanolone, diazepam, and alcohol is reduced
in the luteal phase compared with the follicular
phase.40–42 In addition, patients with severe symptoms
were less sensitive to the given pregnanolone or benzodiazepines compared to patients with more moderate
symptoms.36,38 The findings suggest that patients with
PMS/PMDD develop tolerance to the administration
of GABAA receptor allosteric agonists during the
luteal phase. In an animal model of PMS/PMDD, the
allopregnanolone effect occurs in parallel with an upregulation of the hippocampal ␣4 subunit of the
GABAA receptor and decreased benzodiazepine sensitivity.18 This is in line with the decreased benzodiazepine sensitivity in women with PMDD.41 Animals
with high risk-taking behavior develop withdrawal
symptoms on progesterone treatment.43 The decreased
sensitivity is an indication of the development of tolerance to allopregnanolone. Tolerance to allopregnanolone in rats after 90 minutes of anesthesia has already
been noted.44 There is also a relationship between
tolerance development and change in the GABAA
receptor subunit ␣4 in thalamus.45

CONCLUSION
In conclusion, ovarian steroid hormones are of fundamental importance in inducing negative mood in
PMS/PMDD. We are beginning to develop an understanding of a mechanism where GABAA receptor sensitivity seems to differ in women with PMS/PMDD
and sensitive individuals appear to react to GABAA
receptor agonists in a bimodal inverted U-shaped
manner.

14
The management of PMS/PMDD through
ovarian cycle suppression
Nick Panay and John WW Studd

INTRODUCTION
We have seen in previous chapters that the underlying
cause of premenstrual syndrome/premenstrual dysphoric
disorder (PMS/PMDD) remains unknown, although
cyclical ovarian activity appears to be a key factor.1 A
logical treatment, therefore, is to suppress ovulation
and thus prevent the neuroendocrine changes that cause
the distressing symptoms. The current therapy for PMS/
PMDD is varied and includes psychotherapeutic, cognitive, or hormonal. However, the cornerstone of hormonal treatment relies upon suppression of ovulation
and removal of the hormonal changes that follow ovulation in the luteal phase. When there are no cyclical
hormonal changes during pregnancy, not only are there
no cyclical mood symptoms but also depression is uncommon. There then often follows an episode of postpartum depression when there is a fall of levels of placental
hormones, with a recurrence of symptoms when the
periods return.2
There are now many placebo-controlled studies
showing that suppression of ovulation by increasing
plasma estradiol levels or by down-regulation results in
an improvement in PMS/PMDD. A number of drugs
are capable of achieving this but they are not without
their own side effects, and this may influence the efficacy
of the treatment and the duration for which they may be
given. The purpose of this chapter will be to review the
evidence for the available therapies and offer some
practical advice as to how these preparations can be
incorporated into day-to-day clinical practice.

THE COMBINED ORAL
CONTRACEPTIVE PILL
Although able to suppress ovulation and used commonly
to improve PMS/PMDD symptoms, the combined oral

contraceptive pill (COCP) was initially not shown to be
of benefit in randomized prospective trials.3 This is
probably because the daily progestogen in the secondgeneration pills caused PMDD-type symptoms of its own
accord. A new combined contraceptive pill (Yasmin,
Schering Corporation) contains an antimineralocorticoid and antiandrogenic progestogen, drospirenone.
This has shown considerable promise in the treatment
of PMS/PMDD, as it is devoid of progestogenic side
effects and provides additional benefits from the mild
diuretic and antiandrogenic effect. There are now both
observational and small randomized trial data supporting its efficacy; these data require confirmation with
larger studies.4
More recently, a lower-dose version of this COCP
(Yaz, Schering Corporation) with 20 ␮g ethinylestradiol
and 3 mg drospirenone (24 active, 4 inactive tablets, per
cycle) has been shown to be effective for treating PMDD
in a moderately sized randomized controlled trial of 450
subjects over three treatment cycles.5 There was a significantly greater improvement of the total Daily Record
of Severity of Problems (DRSP) for active treatment compared with placebo (⫺37.49 vs ⫺29.99, p ⬍ 0.001).
Specifically, mood symptoms improved significantly
(⫺19.2 vs ⫺15.3, p ⫽ 0.003). There was a reduction in
daily symptoms of 48% for active vs 36% for placebo
(RR ⫽ 1.7, p ⫽ 0.015).

Practical aspects
If the COCP is used to treat PMS/PMDD, pill packets
should be used back to back (bicycling/tricycling or
continuously) and a break only introduced if erratic
bleeding occurs. Recognizing the benefits of longer
cycle regimens, a four bleed per year COCP has already
been licensed and a no-bleed regimen is planned. Data
are required to confirm the superiority of these regimens
in comparison to traditional regimens.

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PERCUTANEOUS ESTRADIOL (PATCHES
AND IMPLANTS)
The only ovulation suppressant treatment of proven
efficacy in placebo-controlled trials which appears suitable for long-term usage is continuous percutaneous
17␤-estradiol combined with cyclical progestogen. Oral
preparations in the standard estradiol doses found in
hormone replacement therapy (HRT) are not sufficient
to suppress ovarian activity. The use of estradiol patches
was first reported in a study in which a 100 mg subcutaneous implant of estradiol was administered, achieving serum estradiol levels of around 800 pmol/L; this
proved to be highly effective in every Moos Menstrual
Distress Questionnaire (MDQ) cluster of symptoms
compared with placebo.6
Estradiol implants are long-lasting and transdermal
estradiol patches were subsequently used so that treatment could be administered more simply (avoiding a
minor surgical procedure) and be discontinued at short
notice if required. Initially it was found that, 200 ␮g
estradiol patches suppressed ovulation; they were tested
against placebo in a cross-over trial and found to be
highly effective (Figure 14.1).7 The study was a randomized, double-blind, placebo-controlled trial with crossover at 3 months; 20 patients in the active treatment
group received 200 ␮g (two ⫻ 100 ␮g) estradiol patches
followed by placebo and 20 patients were treated in
reverse order. Patients completed the MDQ and Premenstrual Distress Questionnaire (PDQ) daily throughout
the study. After 3 months, both groups showed improvements in MDQ and PDQ scores. In general, patients
who switched from active treatment to placebo had
deteriorating scores, whereas patients who switched from
placebo to active treatment maintained or improved upon
their initial gains. Significant improvements occurred

after changing to active treatment in 5 of 6 negative
MDQ symptom clusters and in 6 of 10 PDQ symptoms.
However, there was concern that estradiol 200 ␮g
twice weekly was too high a dose to be used as longterm therapy. A subsequent observational study8 showed
that 100 ␮g estradiol patches twice weekly were as effective as 200 ␮g twice weekly in reducing symptom levels
in severe premenstrual syndrome. This dosage was better
tolerated in that there was a lower incidence of nausea
and breast tenderness at initiation of treatment. The
most recent randomized controlled study using 100 ␮g
estradiol patches showed efficacy over a longer time
period. This was an 8-month placebo-controlled randomized trial with cross-over at 4 months and a 6-month
extension phase (Figure 14.2).9 What was particularly
interesting about the findings of this trial was that not
only was there a significant improvement in symptoms
over the initial 8 months but also these improvements
continued through the extension phase of the trial.
Although the authors of this chapter believe that
ovulation suppression by transdermal estrogens can be
a first-line therapy for PMS/PMDD, they are surprised
that the original Lancet paper7 of a randomized trial
published 18 years ago has not been replicated. Either
the study is considered perfect or there are other possibly commercial reasons why manufacturers of estradiol
implants and patches have been less enthusiastic about
pursuing a licensed indication for PMS/PMDD than
those producing selective serotonin reuptake inhibitors
(SSRIs).

Practical aspects
Transdermal estradiol patches can be used effectively as
a first-line therapy for PMS/PMDD to treat both psychological and physical symptoms. Although there have

been no clinical studies on the use of estradiol gel in
PMDD, it is clear that adequate estradiol levels can be
achieved and thus a beneficial clinical response would
be expected if patients prefer to use this rather than
patches. Treatment with estradiol should be continued
for a minimum of 1 year, as efficacy may improve even
after the initial 6–8 months. As this is not a cure for
PMS/PMDD, patients should be warned that symptoms
can return when treatment is discontinued.
Mild adverse effects occur in 15–20% of users. These
include nausea, breast tenderness, fluid retention,
increased appetite, and patch site skin reactions. Skin
reactions are less common with the newer matrix patch
systems and with estradiol gel. Patients should be counseled that any adverse effects usually wear off after the
first 6 weeks of use.
Concerns regarding breast and endometrial cancer
risks (as found in menopausal patients) are unfounded in
this age group. The area under the curve (AUC) for
estradiol levels is unchanged (compared with that in
spontaneous cycles), as it is the distribution which is
altered. Note that 100 ␮g patches produce mid-follicular
estradiol levels (250–350 pmol/L) that are entirely
normal in premenopausal women. Clinical observation
shows no evidence of an increased risk of endometrial
or breast carcinoma in premenopausal women using
percutaneous patches and either cyclical progestogen
or a levonorgestrel-releasing intrauterine system (LNG
IUS). However, hard randomized placebo-controlled
trial data in large populations looking at these major
outcome measures over a long period of time are lacking.
There is no evidence that the risk of venous thromboembolism is increased by this treatment and recent data in
menopausal women support this finding.10

Contraception
The observation that estradiol 100 ␮g, producing physiological levels of serum estradiol, was equally as effective as estradiol 200 ␮g in treating PMS, strongly
suggested that the principal mechanism of action was
ovarian suppression. Data have shown that luteal phase
progesterone levels were suppressed to anovulatory
levels by this treatment. However, there are insufficient
data in large enough numbers over a long enough
period of time to recommend estradiol patches as a reliable ovulation suppression method. Thus, additional
contraception should be used with estradiol therapy,
except when LNG IUS is being used for progestogenic
opposition.

Progestogen intolerance
One of the limitations of continuous estrogen therapy
for PMS/PMDD is that the endometrium requires
protection from possible hyperplasia and carcinoma by
the administration of progestogen or progesterone.
Unfortunately, this progestogenic opposition can lead
to a resurgence of PMDD-like symptoms (not usually
as severe as the original symptoms being treated). A
previous study showed that PMDD could be recreated
in postmenopausal women administered cyclical
norethisterone.11
Attempts to avoid this (see Chapter 18) include
reduction of the duration or dosage of progestogen, but
this must be counterbalanced by the small increased
risk of hyperplasia with progestogen restriction. Sturdee
and colleagues showed that 12 days of progestogen
avoids hyperplasia altogether, but a shorter duration

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(10 or 7 days) was associated with a 2–4% risk of
hyperplasia.11 These were data from a study of estrogen
therapy in postmenopausal women and so not directly
relevant. However, a study of PMS/PMDD from the
authors’ unit (unpublished data)9 of longer-term treatment with the 100 ␮g estradiol dosage using a lower
dose of cyclical norethisterone acetate (1 mg) for only
10 days each cycle has shown benefit over placebo for
eight cycles, with continued improvement in a 6-month
extension. Not surprisingly, the incidence of progestogen intolerance was reduced with this regimen. There
were no reported cases of endometrial thickening (a surrogate for endometrial hyperplasia assessed by transvaginal ultrasound) in this study, despite the lower dose
and shorter duration of progestogen.13
Work is now ongoing in the authors’ unit to show if
use of a natural progesterone or LNG IUS (Mirena) as
progestogenic opposition can maximize efficacy while
minimizing PMDD-like side effects. In the interim, it is
possible to use a LNG IUS, progesterone pessaries, or
progesterone gel 8% in the progestogen-intolerant
woman.13,14
There is then clearcut evidence that estradiol can be
used to manage PMS/PMDD by suppressing ovulation.
There is also clear evidence that the LNG IUS protects
from endometrial hyperplasia. Only limited evidence
exists as yet to demonstrate efficacy of the combination
(Domoney et al, unpublished data). No studies have
been undertaken to directly compare hormonal therapy
with drugs such as the SSRIs.

DANAZOL
Cycle suppression may also be achieved using danazol,
an androgenic steroid. Mansel and Wisby first assessed
the effect of danazol on PMS symptoms and showed
benefit only for breast tenderness.15 Other studies have
shown greater benefit.15,16 A relatively recent randomized, double-blind, cross-over study compared three
successive cycles of danazol at a dose of 200 mg bd to
three cycles of placebo:17 28 of 31 women completed at
least one cycle of treatment while recording symptoms.
From this study, the authors demonstrated that danazol
at a dose of 200 mg bd was superior to placebo for the
relief of severe PMS during the premenstrual period for
the main outcome measures. However, this superiority
is muted or even reversed when the entire cycle is considered. This may be explained by the fact that danazol
therapy does have some nuisance side effects that may
interfere with the usual symptom-free late follicular
phase of women with PMS. One solution suggested for
this problem might be to limit treatment to the luteal
phase only. It is clear that luteal phase only treatment

Practical aspects
Danazol is an effective treatment for PMS and patients
should be counseled that it is an option. However, the
potential for masculinizing side effects usually acts as a
deterrent in the majority of women. Thus, due to its
masculinizing side effects, especially at higher, cyclesuppressing doses, danazol is not commonly used for
treatment of premenstrual syndrome. High doses of
danazol reliably suppress ovulation but are more likely
to induce masculinization. Lower doses avoid such side
effects but as ovulation suppression becomes less reliable the risk of pregnancy with the risk of masculinization of a female fetus becomes significant. All women
taking danazol, whatever the dose, should use adequate
contraception.

GONADOTROPIN-RELEASING
HORMONE ANALOGUES
Gonadotropin-releasing hormone (GnRH) analogues
have been successfully employed to suppress gonadal
steroid production in conditions such as breast cancer,
fibroids, and endometriosis. A recent meta-analysis of
GnRH analogues has confirmed their efficacy compared with placebo (Figure 14.3).18 Seventy-one patients
on active treatment were identified in seven trials. The
overall standardized mean difference (SMD) for all
trials was ⫺1.19 (CI ⫺1.88 to ⫺0.51) (Cohen criteria:
0.3 ⫽ small, 0.5 ⫽ medium, 1.0 ⫽ large effect). The
odds ratio (OR) for benefit was 8.66 (95% CI
2.52–30.26). The SMD was ⫺1.43 and OR ⫽ 13.38
(CI 3.9–46) if data were taken only from anovulation
trials. Efficacy of symptom relief was greater for physical
than for behavioral symptoms (physical SMD ⫽ ⫺1.16
(CI ⫺1.53 to ⫺0.79); behavioral SMD ⫽ ⫺0.68
(CI ⫺1.11 to ⫺0.25)) but difference was not significant
p ⫽ 0.484. One trial used low-dose GnRH analogue to
avoid ovulation suppression but did not show clinical
significance over placebo.19
Thus, GnRH analogue therapy results in profound
cycle suppression and elimination of premenstrual symptoms. In practice, lack of efficacy suggests that the diagnosis should be questioned rather than considered a
limitation of therapy. GnRH analogues are usually recommended as second- or even third-line treatment due
to their hypoestrogenic side effects, but in the opinion
of the authors they are extremely valuable as first-line
therapy in women with the most severe PMDD.

Add-back hormone therapy
Menopausal symptoms and osteoporosis limit the use
of GnRH analogues. The use of add-back hormonal
therapy may reduce these side effects and prolong their
use. There has been some debate as to what the best
form of add-back hormone therapy is for women on
long-term GnRH analogues, both from the point of view
of maintaining efficacy and avoiding osteoporosis. Data
show that bone mineral density can be maintained by
use of standard preparations of both cyclical and continuous HRT. Continuous combined therapy or tibolone
is preferable to sequential combined therapy if one is to
minimize the risks of symptom resurgence during the
progestogen phase from PMDD-like progestogenic side
effects.20,21 Overall, the meta-analysis favored neither
GnRH alone or GnRH with add-back ⫽ 0.12 (CI ⫺0.34
to 0.59),18 which means that the highly beneficial effect
of the analogues is not diminished by the addition of
add-back therapy, particularly for tibolone.

Practical aspects
Because symptoms recur with the return of ovarian
function, therapy may have to be continued indefinitely;
this is precluded by significant trabecular bone loss,
which can occur by 6 months’ therapy. The use of GnRH
analogues with add-back estrogen or tibolone can be
protective to the skeleton, but bone density should be
monitored in women using analogues for more than 6
months, as bone loss may still occur in some individuals.22 There is little published evidence to guide management. It seems likely that bone density scanning is

unnecessary for short-term therapy. If therapy is prolonged, then it would seem safest to undertake bone
density scans (ideally by dual energy X-ray absorptiometry) annually throughout therapy, even when add-back
is used. Treatment should be stopped if bone density
declines significantly in scans performed 1 year apart.

PROGESTERONE AND PROGESTOGENS
The efficacy of progestogens and progesterone in the
treatment of PMS/PMDD remains questionable. Progestogens (synthetic progesterone) produce PMDD-like
side effects due to competition for the mineralocorticoid,
androgen, and central nervous system (CNS) receptors.
It is therefore not surprising that the data for their efficacy is poor. On the other hand, progesterone is diuretic,
natriuretic, and is a CNS anxiolytic. As such, there is
some logic to using a progesterone preparation for treatment of PMD/PMDD.13 However, we have seen that no
evidence exists to demonstrate progesterone deficiency
(see Chapter 10) and so if progesterone was effective it
would be pharmacotherapeutic rather than replacement
therapy.

Possible mechanism of action
One of the theories regarding the genesis of PMS/
PMDD symptoms was that symptoms were due to a
progesterone deficiency in the luteal phase. It is known
that progesterone does produce CNS depression and in
very large doses can be anesthetic. It follows that, in
theory, women with symptoms of irritability and agitated

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depression may therefore respond favorably to progesterone. However, the most plausible mechanism of
action is that at high doses, particularly when used
through the whole cycle, progestogens and progesterone can have an ovulation suppressant effect which
can improve symptoms. However, what often happens
when preparations such as depot medroxyprogesterone
acetate are used is that cyclical symptoms are replaced
by lower-grade continuous PMDD-type side effects.
Most studies have shown no benefit. One prospective
randomized study undertaken and published by a pharmaceutical company did show ‘a benefit for both psychological and physical symptoms in the pre-menstruum
with absence of symptoms in the post-menstruum’.23
Patients were randomized to use either progesterone
pessaries (400 mg twice a day) or matching placebo, by
vaginal or rectal administration, from 14 days before
the expected onset of menstruation until onset of vaginal
bleeding for four consecutive cycles; 45 general practitioners identified a total of 281 patients. The main
outcome variables were change in the severity of each
patient’s most severe symptoms and in the average score
of all the patients’ symptoms. The response to progesterone was greater than to placebo during each cycle;
the difference was clinically and statistically significant.
Adverse events of irregularity of menstruation, vaginal
pruritus, and headache were reported more frequently
by patients taking active therapy.
A recent meta-analysis of all published studies meeting
strict methodological criteria for the treatment of PMS/
PMDD failed to confirm benefit with either progesterone
or progestogens in the management of PMS.24 The
objective of this meta-analysis was to evaluate the efficacy of progesterone and progestogens in the management of premenstrual syndrome. Ten trials of progestogen
therapy (531 women) and four trials of progesterone
therapy (378 women) were reviewed. The main outcome
measure was a reduction in overall symptoms of PMS.
All the trials of progesterone (by both routes of administration) showed no clinically significant difference
between progesterone and placebo. For progestogens,
the overall SMD for reduction in symptoms showed a
slight non-significant difference in favor of progestogen
with the mean difference being ⫺0.036 (95% CI ⫺0.059
to ⫺0.014). The meta-analysis of this systematic review
therefore suggested that there was no published evidence
to support the use of either progesterone or progestogen
therapy in the management of premenstrual syndrome.
The evidence for the use of progesterone and progestogens is poor and does not support their continued use for
PMS. There is some justification for undertaking betterdesigned studies in patients with well-defined PMDD
for the established progestogens and progesterone and
for looking at the newer progestogens: for instance,

etonorgestrel, as found in some modern ovulation suppressant progestogen-only contraceptives (e.g. Cerazette,
Organon Laboratories). Whether study of the so-called
natural progesterone preparations should be undertaken is more debatable and should not be conducted
before there are formulations which give rise to consistent elevation of blood progesterone levels.

HYSTERECTOMY AND BILATERAL
SALPINGO-OOPHORECTOMY
A historical perspective
Henry Maudlsey was the first to recognize the association of physical and emotional symptoms with the
woman’s cycle and with great prescience noted the
association of behavioral changes with ovarian cycles:
‘the monthly activity of the ovaries which marks
the advent of puberty in women has a notable
effect upon the mind and body wherefore it may
become an important cause of mental and physical derangement.’
Thus it was clear that the cyclical symptoms of insanity
or menstrual madness were believed to be due to
ovarian function rather than menstruation, and treatment took the form of removal of ovaries. Thus
evolved the original form of ‘ovarian cycle suppression’.
It was not until 1872 that normal ovariotomy – i.e.
removal of normal ovaries – was performed for a disorder or malady which was not essentially gynecological.25 The first surgeon to perform this was Alfred
Hegar of Freiberg, to be followed 7 days later by Lawson
Tait of Birmingham and Robert Battey of Georgia, USA.
At the latter’s insistence, it became known as Battey’s
operation,26 but in Britain, ‘Tait’s operation’ was used,
particularly by his enemies. Battey believed that insanity was, ‘not infrequently caused by uterine and ovarian
disease’. He describes how he had a Southern girl, of
more than unusual beauty, as a patient with cyclical
vomiting and hysteria. If we regard menstrual madness
as severe PMDD, and ovarian ablation by GnRH analogues as a medical castration equivalent to oophorectomy, then there is ample evidence that removing the
ovarian cycle in this way will improve all of the symptom
groups of severe PMDD. These historical events have
recently been reviewed by Studd and found to have great
relevance to our current medical treatment of PMDD.
Although the procedure would have had the desired
effect of curing cyclical monthly symptoms, if the
surgeon had correctly selected his patients, the 19th
century surgeons had no concept of menopausal symptoms or osteoporosis. Thus, this operation would

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MANAGEMENT BY OVARIAN CYCLE SUPPRESSION 127

ultimately be followed by severe medical problems.
Misplaced overenthusiasm for the surgery removed any
sense of good clinical judgment and usually more harm
was done than good.

More recent data
Although total abdominal hysterectomy and bilateral
salpingo-oophorectomy (TAH/BSO) is a common operation for many indications, there are very few data concerning PMDD. Casson et al27 found it to be effective
in 14 patients for physical and psychological symptoms
as well as having a favorable effect on lifestyle, after first
suppressing ovarian steroidogenesis with danazol. Casper
and Hearn28 also showed a dramatic improvement in
mood, general affect, well-being, life satisfaction and
quality of life in another small study of 14 women.
Cronje et al (Figure 14.4)29 subsequently published the
results of 49 such women collected over 10 years from
two busy PMDD clinics, with all but one being symptomfree and enthusiastic about the treatment. Such surgery
is rarely required but is very effective and indeed curative. However, it is significant that some disapproving
correspondence following the Cronje publication29
referred to the 19th century scandal of Battey’s operation. All but one of these women had tried various ineffective medical treatments for a mean of 3.6 years
before referral to the specialist PMS clinic. They were
treated with anovulatory doses of estradiol patches or
implants for a mean of 3 years before problems with
bleeding or progestogen intolerance made surgical
treatment necessary. One patient, the one who refused
any medical therapy, regretted the operation but all
Very dissatisfied
Dissatisfied
Satisfied

others were very satisfied with a complete resolution of
symptoms.
The importance of ovarian function in the causation
and treatment of PMS should be a factor for discussion
with a patient concerning prophylactic oophorectomy
at the time of consenting for hysterectomy.30 Conservation of ovaries does not cure the symptoms of PMDD,
for the patient will still have cyclical symptoms of
depression, irritability, irrational behavior, etc., as well
as cyclical headaches that may be the equivalent of menstrual migraine before surgery. The psycho-protective
value of estrogens compared with progesterone can be
seen in the beneficial response of women with postnatal
depression and perimenopausal depression, the other
components of ‘reproductive depression’.31,32

Practical aspects
Total abdominal hysterectomy and bilateral salpingooophorectomy is the ultimate form of ovulation suppression and the only true cure for PMS, as this
operation removes the ovarian cycle completely. The
procedure is not commonly performed for this indication, as a lesser alternative can usually be found. However,
data suggest a highly beneficial effect in the selected
women undergoing TAH/BSO, the majority of which
are highly satisfied following this procedure and, as
such, it should be offered as a therapeutic option.
Preoperative GnRH analogues, although not mandatory, are a useful test of whether bilateral oophorectomy
(with or without hysterectomy) would be successful in
treating symptoms. This appears to be such a valuable
approach in gynecological practice that it is disappointing that research has not been conducted to provide the
evidence for the value of this ‘GnRH test’. It is essential
that adequate hormone therapy is given (including,
possibly, testosterone replacement) to prevent simply
replacing one set of symptoms with another. Women
who have had a hysterectomy with ovarian conservation will often continue to have cyclical symptoms in the
absence of menstruation (ovarian cycle syndrome).30
Women who undergo bilateral oophorectomy laparoscopically, with conservation of the uterus, can expect a
much less-invasive procedure. But the persistence of the
uterus and therefore, of course, the endometrium,
entails protection of the endometrium and all that that
entails regarding progestogenic restimulation of symptoms. There are no research studies in this area.

CONCLUSIONS
Although the genesis of PMS/PMDD is probably multifactorial, it is likely that through polygenic inheritance

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128 THE PREMENSTRUAL SYNDROMES

and environmental factors certain women are vulnerable
to the neuroendocrine fluctuations which occur in the
ovulatory and premenstrual parts of the normal cycle.33
The logical ways of treating PMS/PMDD would therefore seem to be the stabilization of the ovarian activity
that triggers the symptoms or reducing the neuroendocrinological susceptibility (see Chapter 15). This can
be achieved in a number of ways, as outlined in this
chapter and in the Royal College of Obstetricians and
Gynaecologists (RCOG) guidelines.34 The least invasive and effective means of ovarian suppression is with
transdermal estrogens used continuously, either with a
low-dose cyclical oral progestogen or better still with a
progestogen-releasing intrauterine system. Second-line
therapy with GnRH analogues and add-back hormone
therapy should be used where transdermal estradiol has
not produced adequate symptom relief after a minimum
trial of 3 months. GnRH analogue treatment can be
used as a first-line therapy where the patient’s symptoms
are causing major disruption of her life. Assuming
GnRH analogue treatment is successful, the patient can
continue long-term if using adequate add-back hormone
therapy, but bone density should be monitored annually. Where fertility is not an issue, hysterectomy and
bilateral salpingo-oophorectomy should be offered as a
third-line option, as long as the patient is willing to use
hormone therapy at least until the average age of
natural menopause. This is the only definitive cure for
PMS/PMDD and is highly successful in a very small
number of appropriately selected individuals.
Future work in this area should concentrate on maximizing the benefit of transdermal estrogens by minimizing PMDD-like side effects with local delivery of
low-dose progestogen/progesterone and the use of selective progestogen receptor modulators. It is also imperative that licensing is sought for the treatment of PMDD
with transdermal estrogens and GnRH analogues with
add-back therapy, in order to facilitate the usage of
these truly effective treatments amongst a greater body
of gynecologists, psychiatrists, and interested primary
care physicians.

INTRODUCTION
We have seen in previous chapters that the current
management of severe premenstrual syndrome (PMS)
and premenstrual dysphoric disorder (PMDD) includes
hormonal, alternative, and non-medication therapies
as well as ovarian suppression (see Chapters 14, 15,
and 17). Limited evidence supports the effectiveness of
some of these treatment strategies, particularly the complementary and so-called ‘natural remedies’; in addition, potential side effects and risks involving long-term
use of hormone treatments may limit their use.
Evidence from numerous open-label as well as randomized placebo-controlled trials (RCTs) has clearly
demonstrated the efficacy of the selective serotonin
reuptake inhibitors (SSRIs) and, to a lesser degree, the
serotonin/norepinephrine reuptake inhibitors (SNRIs),
either when used continuously or intermittently. Overall,
the use of these agents has shown excellent efficacy and
minimal side effects. This chapter will summarize this
evidence and will also discuss the potential use of anxiolytics in this population.

ANTIDEPRESSANTS
Of all the neurotransmitters studied to date, serotonin
has been identified as the most plausible candidate to
be relevant in the pathophysiology of PMS and PMDD
(see Chapter XX). It has been suggested that women with
severe PMS or PMDD are more sensitive to the premenstrual decrease in circulating progesterone metabolites. It has been suggested that serotonergic agents
have the potential for enhancing the production of these
metabolites and thus prevent the occurrence of premenstrual symptoms (see Chapters 7, 10, and 12). It
should therefore come as no surprise that pharmacological interventions have focused primarily on such
agents.

A Swedish group of researchers deserves the credit
for being the first to show that a relatively small dose
(25–50 mg) of clomipramine, a non-selective serotonin
reuptake inhibitor, was effective in reducing symptoms
of irritability and sadness in women with severe PMS.1
Subsequent open-label as well as RCTs have all confirmed the efficacy of clomipramine2 as well as of the
SSRIs3–20 and the SNRIs.21,22 Initially most of these
trials reported on continuous daily dosing of the medication (Table 15.1).
It soon became evident that not only do women with
severe PMS or PMDD respond to somewhat lower doses
of these antidepressants as compared with the usual
doses needed in depression or some of the anxiety disorders but also that the onset of action was much shorter
(days rather than weeks). This observation, along with
the fact that premenstrual symptoms are generally limited
to the luteal phase of the cycle, led the same Swedish
group to initiate the first ever study of intermittent
(luteal phase only) administration of clomipramine.23
Again, subsequent open-label as well as RCTs have
confirmed the efficacy of SSRIs24–37 and SNRIs38 when
administered intermittently (Table 15.2).
The form of intermittent dosing that has been evaluated is treatment enduring for the last 2 weeks of the
menstrual cycle. With intermittent or luteal phase dosing,
treatment is initiated around the time of ovulation and
is discontinued 1 or 2 days after the onset of menstruation. Intermittent dosing should not be confused with
symptom-onset therapy, in which treatment begins
immediately after the first appearance of symptoms.26,36
An intermittent dosing regimen is a reasonable choice
for patients with regular menstrual cycles who are able
to adhere to the on/off dosing regimen, for patients with
no evidence of mood symptoms during the follicular phase
(i.e. patients whose symptoms persist throughout the
menstrual cycle), for patients concerned about long-term
adverse effects (e.g. sexual dysfunction), and for patients
who experience few side effects at treatment initiation.

Weekly luteal phase dosing with enteric-coated fluoxetine 90 mg tablets has been reported to be efficacious in one RCT,27 but to our knowledge this dosage
regimen has not been widely disseminated into clinical
practice.
Semi-intermittent dosing is a more complicated
regimen and involves continuous administration of the
SSRI throughout the menstrual cycle, with increased
doses during the luteal phase. Although intuitive, particularly for patients who experience premenstrual worsening of underlying mood and/or anxiety disorders, this
intervention has not been widely assessed in controlled
trials. To date, only one randomized, placebo-controlled
study has examined the efficacy of semi-intermittent
treatment.39
Several studies have also compared intermittent vs
continuous dosing and found either no differences or
advantage of the intermittent dosing39–44 (Table 15.3).
The extent to which different subgroups of women who
suffer from severe PMS/PMDD could preferably benefit
from either continuous or intermittent dosing remains
to be investigated.
So far, clinicians and patients have opted for intermittent vs continuous dosing primarily based on the patient’s
symptom profile and treatment tolerability. Good candidates for intermittent therapy are patients who wish
to limit the amount of medication they take, are not
able to adhere properly to the continuous regimen, have
no mood symptoms during the follicular phase, or are
concerned about long-term adverse effects (e.g. sexual
dysfunction).45 Treatment cost may also play a role in
the option for intermittent treatment. Other alternatives
for patients who are treated intermittently and do not
achieve a robust clinical response include increasing the
dose of the intermittently administered SSRI or switching to continuous SSRI treatment. If mood or anxiety
symptoms emerge during the follicular phase of the
menstrual cycle, strong consideration should be given
to switching to continuous SSRI therapy. Finally, intolerable adverse effects that occur during intermittent
SSRI therapy may be addressed in one of two ways: by
watchful waiting to determine if they resolve over time
or by a reduction in dose. For patients treated with continuous SSRIs and who only achieve suboptimal clinical response, the dose should be increased after the
second menstrual cycle. Adverse effects are managed by
watchful waiting; if this approach is not effective or if
the adverse effect is intolerable, the dose should be
reduced. When dosage reduction is not successful, consideration should be given to switching to intermittent
SSRI administration.
The specificity of the serotonergic antidepressants in
the treatment of PMS/PMDD has been demonstrated in
several comparative RCTs. Sertraline has been compared

to desipramine,20 fluoxetine to bupropion,11 and paroxetine to maprotiline,16 all clearly demonstrating the
lack of efficacy of the non-SSRIs. Preliminary results
have also shown that L-tryptophan, a serotonergic precursor, is an effective treatment for PMS,37 whereas
lithium is not. Treatment with nefazodone, a serotonin
modulator, has been shown initially to have some beneficial effect25 but in a subsequent RCT, nefazodone
was not more effective than placebo.29 The effectiveness
of milnacipran, a presynaptic SNRI, has recently been
demonstrated in three women with PMDD who were
intolerant to SSRIs.46 Overall, the response rate in most
RCTs for clomipramine, the SSRIs and the SNRIs is
ⱖ60% with a standardized mean difference in favor of
the active drug (for reviews see also References 45,
47–49). To date, no evidence supports a differential treatment response to either SSRIs or SNRIs for patients
with PMDD.
Several of the larger RCTs have also clearly demonstrated that the improvement is not only in the
behavioral/psychological symptoms of PMS/PMDD
(in particular irritability) but also in the physical symptoms (breast tenderness and bloating) (e.g. References
16, 17, 19, 44, 49, and 50) as well as in the psychosocial
domain.44,51,52 Interestingly, premenstrual headaches
do not appear to benefit from treatment with these
agents. The side-effect profile and compliance reported
in these studies do not differ significantly from those
reported in studies using the same medications for other
indications. Nonetheless, intermittent and low doses of
clomipramine, SSRIs, and SNRIs, when used in the treatment of PMS/PMDD, seem to reduce the burden of side
effects. The concern that intermittent dosing, especially
of the antidepressants with a relatively short half-life,
might cause withdrawal symptoms or the discontinuation syndrome has also been evaluated. The studies of
intermittent dosing report neither a high frequency of
initial side effects each time the medication is restarted
nor any marked discontinuation symptoms.53 The lack
of significant withdrawal or discontinuation symptoms
seen with intermittent dosing may be related to its unique
mechanism of action (possibly GABA-a mediated), by
which no prolonged exposure is needed to promote the
therapeutic effect. In fact, subjects treated with intermittent dosing of SSRIs and SNRIs not only fail to
experience discontinuation symptoms but also show
improvement of symptoms that continues into the early
follicular phase.38,54
Adverse drug–drug interactions, especially with drugs
competing for the same microsomal systems in the liver,
are nevertheless potentially dangerous during intermittent dosing, as much as when used continuously. Given
that PMS/PMDD affects women during their reproductive years, it is important to note that there is no

N ⫽ the number of women who were on the active compound.
Conclusion: ⫹⫹, statistically significant improvement vs placebo; ⫹, quality of evidence limited but positive outcome; ⫺, no statistically significant improvement vs
placebo; I ⱖC: intermittent equal to or better than continuous.

clinical evidence that concomitant use of oral contraceptives and antidepressants affects the safety or efficacy
of either agent.55 There is also no evidence of ovulation
disturbance in women using SSRIs or SNRIs, although
a dose-dependent change in cycle length in women with
PMDD treated with continuous dosing of fluoxetine
has been noted.56
Despite the chronicity, symptom severity, and burden
of illness associated with severe PMS/PMDD, RCTs have
focused only on acute phase therapy. Most studies report
on improvement (not remission) of symptoms after 2–3
treatment cycles only and it is therefore not known
whether women are able to stop medications after a
period of time and remain well. It is also not known
whether the efficacy of these interventions wanes over
time, or whether the rapid remission of symptoms could
result in better long-term treatment outcome. Studies
are needed to identify whether or not some women
develop tolerance to the SSRI over time that necessitates increases in dosage or switch to another medication, and whether or not some women stay in remission
for a period of time following SSRI discontinuation.
Nevertheless, preliminary data suggest that there is a
recurrence of symptoms after the cessations of shortterm (three cycles) treatment57 and that long-term fluoxetine treatment is effective and well-tolerated.58
All the studies reported here have excluded the younger
age group of adolescents (12–18 years of age), who are
nevertheless known to suffer from PMS/PMDD.59
Thus, there is no evidence-based information regarding
the efficacy of these interventions for this age group,
and regulatory agencies around the world have
excluded them when granting the use of SSRIs for this
indication.

than 40 studies, both open-label and RCTs, using clomipramine, SSRIs, or SNRIs, there is now ample evidence
that supports the beneficial role that these medications
have in this condition. Both continuous and intermittent dosing are believed to be effective, but the decision
as to which regimen to use has to be made on an individual basis. Continuous dosing should be reserved for
women with a history of comorbid anxiety or depressive disorders or for women who experience concurrent
subsyndromal (underlying) anxiety or mood symptoms
throughout the entire cycle. These women may also
benefit from semi-intermittent dosing, i.e. dose increase
during the late luteal phase (e.g. Wikander et al39).
Continuous dosing may also be the choice for women
who may find it easier to adhere to the daily dosing
regimen. Intermittent, or even symptom-onset dosing,
may be more appropriate for women with ‘pure’ PMS/
PMDD, i.e. those whose symptoms are limited to the
late luteal phase only, with a definite ‘on-off’ presentation. This should also be the option for women who
prefer not to take medication throughout the entire cycle
or who experience bothersome side effects (especially
sexual dysfunction), which can be minimized with
intermittent dosing.
The choice of anxiolytics is limited, but both alprazolam and buspirone have been shown, primarily, to
reduce premenstrual irritability. These medications, to
be used intermittently or even for a couple of days, on
a ‘as-needed basis’ (prn), should be reserved mostly for
women who are intolerant to the serotonergic or noradrenergic agents and they should be used cautiously
due to their addictive nature.

REFERENCES
ANXIOLYTICS
alprazolam60–65

buspirone29,66

The anxiolytics
and
have demonstrated efficacy in some but not all trials
(Table 15.4); however, the magnitude of the therapeutic
effect is not as high as for the SSRIs/SNRIs. The sideeffect profile and the potential for dependence, especially with alprazolam, make them a less desirable
option, to be used preferably as a third line of choice.

CONCLUSIONS
It is now more than 15 years since the first reports
appeared in the literature on the effectiveness of
serotonin-enhancing agents in treating women with
severe premenstrual symptoms. Based on data to date
on more than 3000 women who participated in more

INTRODUCTION
It is far from easy to define complementary and alternative medicine (CAM). Describing it by what it is not (e.g.
scientifically plausible or tested, not taught in medical
school) was always unsatisfactory and is becoming
increasingly incorrect. Intuitively, we seem to know what
CAM is (Table 16.1), but this is clearly not enough.
One definition which is widely used describes CAM as:
Diagnosis, treatment and/or prevention which
complements mainstream medicine by contributing
to a common whole, by satisfying a demand not met
by orthodoxy or by diversifying the conceptual
frameworks of medicine.1
Definitions of CAM are difficult and problematic, not
least because CAM entails a bewildering array of therapeutic and diagnostic modalities (Table 16.2). Despite
this heterogeneity, there are common features of CAM,
which include:
●
●
●
●

●

●
●
●

emphasis is on holism
treatments are alleged to be natural
treatments are often assumed to be harmless
treatments are often individualized according to the
characteristics of each patient
there is much emphasis on the body’s power to heal
itself
a long tradition of usage for most modalities
by and large, CAM is private healthcare
it may be administered by a practitioner or selfadministered.

CAM has become increasingly important for healthcare professionals, simply because patients are voting
with their feet and their wallets in favor of it.2 Many
healthcare professionals, however, remain sceptical about
its value and few have sound knowledge of the subject.

But, because of its popularity, it seems desirable that all
healthcare providers are aware of the basics of CAM:
we may love or hate CAM, but if patients use it, we
need to know about it.

PREVALENCE
About 65% of all US citizens seem to try at least one
form of CAM within a year.3 These figures can be even
higher in patient populations, especially those suffering
from chronic conditions. Virtually all surveys agree that
women use CAM significantly more often than men.
Women suffering from premenstrual dysphoric disorder
(PMDD) frequently try CAM.4,5 Popular choices include
exercise (arguably not CAM), vitamins (arguably not
CAM), other dietary supplements (including herbal medicine), meditation, yoga, acupuncture, massage, homeopathy, and chiropractic.4,5

REASONS FOR POPULARITY
Many conventional healthcare providers are puzzled by
the current popularity and commercial success of CAM.
Surely, conventional medicine is more effective than ever
before – so why do people turn towards ‘alternatives’?
The first important point to make here is that CAM is
not normally employed as an alternative. In the vast
majority of cases, it is used as an ‘add on’ to conventional
healthcare. The term ‘alternative medicine’ is therefore
inappropriate. The second important point is that no
single reason or set of reasons for the popularity of CAM
exist. Notwithstanding these caveats, research has
identified numerous motivators for trying CAM. They
can be categorized into positive (pull) and negative (push)
factors (Table 16.3).6 Depending on the precise circumstances, the relative importance of these factors varies.

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142 THE PREMENSTRUAL SYNDROMES

Table 16.1 ‘Tongue in cheek’ definitions of CAM from different perspectives
Perspective

Definitions

The patient

Healthcare I’ve used for years and don’t dare tell my doctor about

The doctor

Type of medicine many of my patients use (without telling me) and I know nothing about

The CAM provider

Healthcare that is universally appreciated by patients but suppressed by ‘the establishment’

The regulator

Type of medicine which is outside our control

The manufacturer

Supplements which sell very well, even without investment into research

The scientist

Implausible treatments which can help patients through a powerful placebo effect

The politician

Private medicine which is popular and can win votes – should not be researched seriously;
however, this might show efficacy (in which case the government ought to pay for it)

Table 16.2 Some commonly used modalities in CAM
Name

Description

Acupuncture

Insertion of a needle into the skin and underlying tissues in special sites, known as points,
for therapeutic or preventive purposes

Aromatherapy

The controlled use of plant essences for therapeutic purposes

Bach flower
remedies

A therapeutic system that uses specially prepared plant infusions to balance physical and
emotional disturbances

Biofeedback

The use of apparatus to monitor, amplify, and feed back information on physiological
responses so that a patient can learn to regulate these responses. It is a form of
psychophysiological self-regulation

Chelation therapy

A method for removing toxins, minerals, and metabolic wastes from the bloodstream and
vessel walls using intravenous EDTA (ethylenediaminetetra-acetic acid) infusions

Chiropractic

A system of healthcare which is based on the belief that the nervous system is the most
important determinant of health and that most diseases are caused by spinal subluxations
which respond to spinal manipulation

Craniosacral therapy

A proprietary form of therapeutic manipulation which is tissue-, fluid-, membrane-, and
energy-orientated and more subtle than any other type of cranial work

Herbalism

The medical use of preparations that contain exclusively plant material

Homeopathy

A therapeutic method using preparations of substances whose effects when administered
to healthy subjects correspond to the manifestations of the disorder (symptoms, clinical
signs, and pathological states) in the unwell patient

Hypnotherapy

The induction of a trance-like state to facilitate the relaxation of the conscious mind and
make use of enhanced suggestibility to treat psychological and medical conditions and
effect behavioral changes

Massage

A method of manipulating the soft tissue of whole body areas using pressure and traction

(Continued)

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COMPLEMENTARY AND ALTERNATIVE THERAPIES 143

Table 16.2 (Continued)
Name

Description

Naturopathy

An eclectic system of healthcare, which integrates elements of complementary and
conventional medicine to support and enhance self-healing processes

Osteopathy

A form of manual therapy involving massage, mobilization, and spinal manipulation

Reflexology

A therapeutic method that uses manual pressure applied to specific areas, or zones, of
the feet (and sometimes the hands or ears) that are believed to correspond to areas of the
body, in order to relieve stress and prevent and treat physical disorders

Relaxation therapy

Techniques for eliciting the ‘relaxation response’ of the autonomic nervous system

Spiritual healing

The direct interaction between one individual (the healer) and a second (sick) individual
with the intention of bringing about an improvement or cure of the illness

Yoga

A practice of gentle stretching, exercises for breath control, and meditation as a mindbody intervention

Much of the popularity of CAM amounts to a criticism of conventional healthcare. This can be seen as a
backlash from the spirit of the mid-20th century when
science was expected to solve most problems. Reality
turned out to be different. Many consumers now feel
disappointed that many medical conditions (including
PMDD) cannot be cured or adequately alleviated (i.e.
without side effects); CAM, on the other hand, is ‘free’
of safety problems – at least this is what proponents
incessantly claim.

THE EVIDENCE FOR OR AGAINST CAM
Even though sometimes denied by proponents of CAM,
most therapies can be tested for efficacy/effectiveness
in randomized clinical trials (RCTs). Occasionally, the
standard RCT design requires adaptation to fit the
demands of CAM,7 but there are no compelling reasons
why CAM should defy scientific testing in principle.
The following discussion regarding the effectiveness of
CAM to treat PMDD will therefore be based on evidence from clinical trials and (where available) systematic reviews of such studies.

Acupuncture/acupressure
A systematic review included four controlled clinical
trials (CCTs) of acupuncture or acupressure for dysmenorrhea (not PMDD).8 Even though they all generated results suggesting that acupuncture does in fact

Biofeedback
Vaginal temperature feedback (12 weekly sessions) was
compared with no treatment in two RCTs with 30
women.9 Biofeedback alleviated both physiological and
affective symptoms. However, methodological shortcomings of these studies cast doubt on the validity of
their findings.

Evening primrose
A systematic review of evening primrose (Oenothera
biennis) oil included seven uncontrolled studies as well
as four randomized and placebo-controlled RCTs.14
None of these investigations had large samples and most
trials had other serious methodological weaknesses. The
three most rigorous RCTs were all negative. The conclusion drawn from this evidence was that evening primrose oil seems to be of little value for PMDD. Evening
primrose oil has been marketed extensively for PMS,
PMDD, and for cyclical mastalgia and, although the
evidence was limited, it was licensed for cyclical breast
symptoms.

Herbal medicine

Ginkgo

Chaste tree
Chaste tree (Vitex agnus-castus) extracts have been tested
in several uncontrolled studies. The results were invariably
positive. In a large (n ⫽ 1634) study, for instance, 81%
of all patients rated themselves ‘much better’.10 The
results of double-blind RCTs (Table 16.4) are, however,
not uniform.11–13 One placebo-controlled RCT11 failed
to demonstrate efficacy whereas the other such study13
suggested that chaste tree extract does alleviate symptoms. One RCT12 compared the herbal extract to vitamin
B6. The results suggested equivalence, but it is unclear
whether this indicates that both are similarly effective
or ineffective. The value of chaste tree extracts has thus
not been proven beyond reasonable doubt.

Ginkgo (Ginkgo biloba) was investigated in a doubleblind RCT with 163 women suffering from PMDD.15
Patients were given either placebo or 160 mg ginkgo
extract daily for 2 months. The results suggested that
regular ginkgo intake may be helpful for breast pain,
but not for other symptoms of PMDD.

Homeopathy
Two double-blind, placebo-controlled RCTs of classical homeopathy have been published. In the first one,
stringent exclusion criteria led to the sample being too
small (n ⫽ 10) for generating meaningful results.16

The other study comprised 105 patients treated over 3
months.17 By the end of this treatment, symptom scores
were lower in the homeopathically treated group compared with the placebo group. There was also less use
of tranquillizers and analgesics and fewer work days
lost than in the placebo group. Vis-à-vis these contradictory findings, no definitive conclusions about the
value of homeopathy for PMDD are possible.

Massage
An RCT of massage therapy for 24 women with PMDD
reported some improvements in symptoms immediately
after massage sessions and after 1 month of treatment.
However, the mood symptoms that are central to PMDD
were not lowered at 1 month. Relaxation was used as a
control, but intergroup analyses were not conducted.18
The effectiveness of massage for PMDD therefore remains
speculative.

Reflexology
An RCT (n ⫽ 35) of reflexology applied once weekly
for 2 months reduced both somatic and psychological
PMDD symptoms significantly more than sham reflexology, which involved treating points unrelated to premenstrual symptoms.19 This study needs independent
replication before recommendations can be made.

Relaxation
Progressive muscle relaxation training (twice weekly for
3 months) alleviated physical symptoms of PMDD in
an RCT (n ⫽ 46) compared with the control interventions of reading and charting symptoms.20 For women
with severe complaints, there were also improvements

in emotional symptoms. Independent replications of these
data are required.

Spinal manipulation
A cross-over RCT of chiropractic manipulation included
25 PMDD patients. Superior results were noted for
spinal manipulation compared with a sham treatment.21
However, improvements were greatest with whichever
intervention was received first. Therefore the perceived
benefits may not be due to specific effects of spinal
manipulation.

Dietary supplements

Calcium
Calcium supplementation has been demonstrated to be
superior to placebo for most types of PMDD symptoms
in two double-blind RCTs (Table 16.5).22,23 The second
of these trials is impressive in terms of size (n ⫽ 466)
and methodological rigor and provides promising evidence in favor of calcium.

Magnesium
Two small double-blind RCTs of magnesium supplements have indicated some benefits over placebo.24,25
However, the type of symptoms that improved was different in each study. The data are therefore not compelling and require independent replication.

Neptune Krill
Neptune Krill Oil has been compared to fish oil in an
RCT with 70 women.26 The results suggest that both
have similar effects on dysmenorrhea and symptoms of

PMDD. However, one cannot be sure that both were
equally effective or ineffective.

Potassium
Potassium was investigated as a therapy in a nonrandomized, placebo-controlled trial.27 The results
showed no effect on PMDD symptoms or premenstrual
weight gain.

Vitamin E
Vitamin E has been investigated in two double-blind,
placebo-controlled RCTs.30,31 Although both show positive results for some PMDD symptoms, the overall evidence is ambiguous and more research is required.

Other therapies

Aerobic exercise
Vitamin B6
Vitamin B6 is a cofactor in the synthesis of serotonin
from dietary tryptophan. It is self-prescribed extensively. The RCT evidence for vitamin B6 has been subjected to systematic review. A meta-analysis pooled the
data of nine double-blind, placebo-controlled RCTs.
Greater effect than placebo for overall symptoms and
premenstrual depression were noted. The authors cautioned, however, that conclusions must remain limited
due to the low quality of most trials. The authors also
advised that doses in excess of 100 mg/day were not
justified due to neurological adverse effects.28 Combining
vitamin B6 and magnesium reduces anxiety-related symptoms of PMDD.29

A relatively large body of evidence from questionnaire
studies, non-randomized trials, and case–control studies
suggests that aerobic exercise training may help prevent
or alleviate premenstrual symptoms (e.g. References
32–35).

Qi-therapy
Qi-therapy has generated encouraging results in two
RCTs from the same research group.36,37

SAFETY ISSUES
Patients are continually being misled into believing (e.g.
by the media or by the ∼40 million websites promoting
CAM) that CAM is natural and therefore safe. This
misinformation can be dangerous, as none of the treatments is totally devoid of risks (Table 16.6). This is
clearly not the place to review this complex area; the
reader is referred to comprehensive overviews published elsewhere.2,38

CONCLUSIONS
Many CAM treatments are being promoted and used
for PMDD: only some of them have been submitted to
clinical trials. Frequently, the methodological rigor of
these studies is wanting and, for each modality, trial
data remain scarce. The most promising results so far
suggest that acupuncture, calcium supplements, or
vitamin B6 might alleviate some of the symptoms of
PMDD.

Less obvious risks
●

●

●

Use of CAM as a true alternative to effective
healthcare
Reliance on unreliable diagnostic techniques used
by CAM providers
Cost of ineffective treatments

INTRODUCTION
The clinical approach to evaluation and management
of premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) involves taking an accurate
history, prospective daily symptom monitoring to
establish the diagnosis, patient-specific initial medical
or psychological therapy, and adequate follow-up with
appropriate alterations in the treatment plan. A typical
patient can present with premenstrual irritability, mood
swings, anxiety and/or depression, and physical symptoms that may include breast tenderness, bloating,
fatigue, appetite, and sleep alterations, or difficulty
concentrating; these conditions result in significant
overall interference with daily activities or social interactions. As the symptoms are not unique in their nature
but only in their timing, the diagnosis should be made
only after the patient completes daily recording of bothersome symptoms for 2–3 consecutive months. However,
a detailed psychiatric interview by an appropriately
trained professional may rule out underlying affective
disorder. This may be a useful compromise when only
retrospective information is available.1 Various medical
and affective disorders included in the differential diagnosis must be excluded. Current management strategies
include education and self-care, calcium supplementation, and the choice of a number of psychotropic agents
that augment serotonin, administered either throughout the cycle or during the luteal phase alone. Pharmacological options include selective serotonin reuptake
inhibitors (SSRIs), serotonin/norepinephrine reuptake
inhibitors (SNRIs), serotonergic tricyclic antidepressants, or hormonal approaches that prevent ovulation,
such as some oral contraceptives, gonadotropin-releasing
hormone agonists (GnRH agonists), danazol, and highdose estrogen. Psychological approaches, including
cognitive/behavioral and relaxation therapy, may also

be effective. The treatment plan should be designed
according to the patient’s specific symptoms, past pharmacological treatment experiences, and other current
and past health and contraceptive needs.

CLINICAL EVALUATION
Diagnostic criteria
One of the limitations in establishing the diagnosis of a
premenstrual disorder is the lack of universally accepted diagnostic criteria. Factors generic to the diagnosis
of PMS and PMDD are that (1) the somatic, affective,
and/or behavioral symptoms only occur in ovulatory
women and that (2) the symptoms must recur cyclically
in the luteal phase of the menstrual cycle and resolve by
the end of menses, leaving a symptom-free interval in
the late follicular phase, before ovulation.
The American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin on PMS
containing diagnostic criteria.2 According to these criteria, the diagnosis of PMS requires that a woman must
have one or more of the affective or somatic symptoms
listed in Table 17.1.
The PMS criteria additionally specify that the symptoms must occur during the 5 days before menses in
each of three prior menstrual cycles, with relief by day
4 of menses. This cyclic pattern must be confirmed in at
least two consecutive months of prospective symptom
charting. The symptoms must be bothersome, with the
woman experiencing dysfunction in social and/or occupational spheres. These recurring symptoms must be
present in the absence of pharmacological therapy,
including hormones, or use of alcohol or drugs. Other
psychiatric and medical disorders must have been
excluded as a potential cause of the symptoms.3,4

PMS can be diagnosed after the patient prospectively
documents at least one of the affective or somatic
symptoms during the 5 days prior to menses for three
menstrual cycles. Symptoms should be of such severity
as to impact social or economic performance. Symptoms
should abate during the first 4 days of the menstrual
cycle and not recur until at least cycle day 13. There
should be no concomitant pharmacological therapy,
hormone ingestion, or drug or alcohol abuse.
Adapted from ACOG.2

Diagnostic criteria for PMDD, found in the Diagnostic and Statistical Manual of Mental Disorders, fourth
edition, text revision (DSM-IV-TR), are more specific
and include endorsement of five or more of the symptoms listed in Table 17.2, with at least one being a core
symptom.5
Further PMS criteria are that the symptoms must be
present during the last week of the luteal phase in most
of the woman’s menstrual cycles in the previous year,
be relieved within the first few days of the follicular
phase of the cycle, and must not have recurred during
the week that follows menses. The criteria must be
confirmed by prospective daily ratings for at least two
consecutive symptomatic cycles. The symptoms must
not represent an exacerbation of another disorder, such
as a depressive or anxiety disorder, substance abuse, a
personality disorder, perimenopause, or thyroid disease,
although they can be superimposed on such a disorder.
A diagnosis of PMDD requires that the symptoms be
severe enough to interfere with the woman’s work,
social interactions, or usual activities. The National
Institute of Mental Health also defines premenstrual
changes as showing at least a 30% increase in symptom
intensity during the late luteal phase of the cycle (6 days

Experience five or more symptoms, including at least one core symptom:
●
Markedly depressed mood, hopelessness, self-deprecating thoughtsa
●
Marked anxiety, tensiona
●
Marked affective labilitya
●
Persistent and marked anger or irritabilitya
●
Decreased interest in usual activities
●
Subjective sense of difficulty in concentrating
●
Subjective sense of being out of control
●
Lethargy, easy fatigability
●
Marked change in appetite
●
Hypersomnia or insomnia
●
Other physical symptoms, such as breast tenderness-headache.
Report symptoms during the last week of the luteal phase, with remission within a few days of the onset of menses
Document absence of symptoms during the week following menses
Demonstrate marked interference of symptoms with work, school, or social activities and relationships
Symptoms are not an exacerbation of another disorder
Prospective daily ratings confirm three of the above criteria during at least two consecutive symptomatic menstrual
cycles.

aCore

symptoms; PMDD can be diagnosed when, for most of the 12 cycles, the above criteria are met. Adapted from the
Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV). Washington DC: American Psychiatric
Association; 1994: 715–18.

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prior to menses) compared with the follicular phase
(days 5–10 of the cycle).6

Table 17.3 Differential diagnosis of premenstrual
disorders3

The diagnostic process
There are no specific diagnostic tests for PMS or PMDD.
Therefore, the diagnostic process is one of exclusion
based on a clinical interview, physical examination,
and prospective daily recordings. A comprehensive
assessment is essential, exploring medical, gynecological, psychosocial, and psychosexual history, as well as
substance abuse, domestic violence and life stressors, to
determine the presence of past or current menstrualrelated disorders, psychiatric disorders, or medical
conditions (Table 17.3). It is very useful to perform
assessment during the follicular phase to assess mood,
cognition, and general level of functioning when premenstrual symptoms should be absent. An alteration in
mental state during the follicular phase would suggest
the necessity of a comprehensive psychiatric evaluation.7,8 A thorough history, eliciting all bothersome
premenstrual symptoms, is adequate, but a retrospective history or questionnaire, such as the Premenstrual
Assessment Form (PAF), can be used.9 The clinician
must establish that the patient is ovulating, particularly
if menses are not regular (ovulatory cycles are generally
about 25–32 days in length.) Symptoms such as
headache/migraine, fatigue, abdominal or breast pain,
bloating, and vaginal spotting, presenting premenstrually, may be a result of other medical conditions.
Symptoms of a depressive disorder, anxiety disorder,
or personality disorder will not demonstrate a purely
cyclic pattern, with a consistent asymptomatic phase
before ovulation, although these disorders often worsen
premenstrually.10
A thorough physical examination should be completed, including a breast and pelvic examination.
Gynecological issues to be assessed include pregnancy,
postpartum status, perimenopause, cycle irregularity,
polycystic ovary syndrome, chronic pelvic pain, and
endometriosis; fibrocystic disease, galactorrhea, and
breast cancer should be evaluated in a woman who
presents with breast symptoms. If a woman is using an
oral contraceptive that suppresses ovulation, the symptoms experienced prior to the monthly bleeding are not
PMS but could be attributed to hormone withdrawal
associated with the hormone-free interval in the pill
regimen.11 Over age 40 years old, symptoms such as
dysphoria, breast tenderness, headache, and sleep disturbances occurring during the premenopausal period
should be differentiated from those of the perimenopause. The history and physical examination might
prompt specific blood or radiological tests, such as
complete blood count, thyroid- or follicle-stimulating

hormones, chemistry levels, and breast or pelvic imaging
studies, although no specific tests are mandatory.
At the initial visit, educational information is imparted concerning lifestyle changes and treatment strategies
to decrease premenstrual symptoms and reduce stress,
as well as how to keep a prospective chart of symptoms

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152 THE PREMENSTRUAL SYNDROMES

for a period of 2 months. Some type of severity rating
must be a part of these charts, such as using a scale
ranging from ‘0’ for no symptoms to ‘4’ for severe
symptoms, for example, and noting those that interfere
with functioning. Various validated diaries will be discussed below.
The woman should then evaluate the impact of
various lifestyle approaches during the recording of her
symptoms. In order to minimize the her disappointment with the prospect of leaving the office without
specific therapy, the following points should be made:
1.

2.

3.
4.

The diagnosis usually requires prospective monitoring to rule out affective disorders that would
require daily, not luteal, therapy with specific psychotropics, as opposed to hormonal agents.
Treatment options will be better tailored to her
symptom type and timing and to her other gynecological needs, such as treatment of dysmenorrhea or contraception.
Lifestyle change, stress reduction, and daily charting
may be effective treatment.
Treatment is usually necessary for most of the
reproductive years and thus the approach using the
lowest dose of a pharmacological agent specific for
the natural symptom duration and severity, and
providing the best side-effect profile is preferable.

The second visit consists primarily of reviewing the
symptom diary, establishing a diagnosis of a premenstrual disorder and choosing the optimal treatment
approach. Dividing a woman’s symptom ratings into
the premenstrual, menstrual, and postmenstrual phases
will determine if a temporal relationship exists between
symptoms and menses.

Daily Rating Forms
There is a lack of agreement on the practicality of daily
prospective symptom rating due to the amount of time
required and delay in therapeutic interventions while
symptoms are recorded. Some consider that an interview by an appropriately trained psychiatrist could
suffice to exclude an underlying psychiatric disorder
and could replace daily symptom recording. However,
this is not universally accepted (particularly for research)
and is contrary to the guidance in DSM-IV. Daily
symptom diaries can also be therapeutic, increasing
patient involvement and adherence to management
strategies and allowing for the individualization of
treatment. When the woman is unable to provide
prospective data, the spouse/partner can keep a calendar of premenstrual observations to establish the type,
severity, and pattern of symptoms. One must recognize

the limitations of self-reported retrospective measures.
Biases include sociocultural, environmental, and patient
and family expectations. Patients may forget to fill out
the calendar daily and use recall to complete the missed
days. The use of an electronic, voice-activated device
that allows the patient to record daily while blinding
prior entries may assist in obtaining more accurate
information.12
Some clinicians may prefer to use a visually graphic
evaluative tool. A visual analog scale (VAS) requires the
patient to rate specific symptoms on a line, 100 mm in
length. The anchor lines at the left- and right-hand ends
of the scale represent ‘0,’ or no symptoms, and ‘100,’
extreme symptoms. The VAS was recently revised to
more nearly reflect the DSM-IV-TR criteria for PMDD;
it includes the four core symptoms (irritability, tension,
depressed mood, and mood lability) and seven symptom
clusters (decreased interest in usual activities, difficulty
concentrating, lack of energy, appetite change, change
in sleep, feeling out of control, and somatic symptoms).1
The days most appropriate for calculating the follicular
and luteal score in a clinical setting are cycle days 7
through 11 for the follicular score and days 16 through
22 for the late luteal score.13
The Calendar of Premenstrual Experiences (COPE)
is a daily diary that includes 22 symptoms commonly
reported by women with PMS.14 The symptoms are
rated on a four-point scale, ranging from ‘0’ for no
symptoms to ‘3,’ which indicates that the symptoms are
severe and the woman is unable to perform normal
activities. PMS is diagnosed when the total of the
points for the luteal phase (i.e. the last 7 days of the
cycle) is at least 30% greater than the sum of points for
the follicular phase of the cycle (i.e. days 3 through 9 of
the cycle).
The Daily Record of Severity of Problems (DRSP) is
a daily diary that has been developed for use in the
diagnosis of PMDD.15 The 11 symptoms included in
the DSM-IV-TR diagnostic criteria for PMDD are
described in 21 separate items. In addition, the DRSP
includes three symptom-related areas of functional
impairment that are necessary for the diagnosis of
PMDD. Women are also instructed to list the days of
bleeding. Symptoms are rated on a scale ranging from
1 ⫽ not at all to 6 ⫽ extreme. The individual and
summary scores in the DRSP have high reliability and
tend to be sensitive to treatment differences.
Severe PMS and PMDD can be difficult to differentiate
from the premenstrual exacerbation of a medical or
psychiatric disorder. At present, a diagnosis of PMDD
specifically requires the exclusion of any psychiatric
disorder that might explain the symptoms.5 In screening for psychiatric disorders, it is especially important
to determine any past or current episodes of depressive,

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anxiety, or bipolar disorders, postpartum illness, eating
disorders, substance abuse, or personality disorders.
Women with PMDD commonly have past episodes,
postpartum episodes, or a family history of depressive
and/or anxiety disorders.10 Several studies have reported that women with severe premenstrual symptoms
have a greater possibility for psychopathology and other
significant difficulties.16–19
PMDD and psychiatric disorders may also be coexisting conditions. There is a high comorbidity of PMS
and PMDD with anxiety, depressive, and other psychiatric disorders,17 although PMDD is a distinct diagnostic entity separate from other affective disorders. The
patient may have a history of mood disorder with
current PMDD or the patient may have no mood disorder outside of PMDD. Symptoms of major depressive
disorder, anxiety disorder, or personality disorder will
not demonstrate a cyclic pattern with a constant
symptom-free interval prior to ovulation.

Therapeutic approaches
Non-pharmacological or over-the-counter medical
approaches are recommended during the 2-month prospective rating period. There is level A and B evidence
for each of several modalities, including exercise,
dietary supplements, and psychological interventions.
Even daily recording can be therapeutic for the patient
and her family.
Initiation of or increase in exercise, particularly the
aerobic variety, can reduce premenstrual mood and
physical symptoms and has other obvious potential
health advantages. At least 3 days per week, 20–30
minutes of aerobic exercise should be performed.20,21
Dietary changes or calcium supplementation can be
initiated. Calcium carbonate, 1200 mg/day in divided
doses, has also shown efficacy in at least one randomized controlled trial for PMS.22 Furthermore, in 105
women meeting DSM-IV criteria for PMDD, there was
a statistically significant negative relationship between
milk consumption and the following premenstrual
complaints: abdominal bloating, cramps, craving for
some foods, and increased appetite.23 Vitamin supplementation with pharmacological doses of vitamin B6
can also be initiated if the patient is not already taking
a vitamin supplement. Vitamin B6 intake in excess of
100 mg/day is not recommended and can be neurotoxic.24 A review of published and unpublished randomized placebo trials of the use of vitamin B6 in PMS
concluded that doses up to 100 mg/day are likely to be
helpful in the treatment of premenstrual symptoms,
including depression.25 Limited data indicate a possible
benefit of a complex and simple carbohydrate-containing
beverage taken twice per day premenstrually, allowing

for greater absorption of L-tryptophan, the amino acid
precursor of serotonin.26,27 However, the availability of
this product is limited and each serving contains at least
200 calories.
For women with premenstrual mastalgia, abdominal discomfort, and headache, non-steroidal antiinflammatory medication is helpful, but limited data
investigating small groups of women given mefenamic
acid or naproxen sodium suggest the psychological
symptoms of PMS may also improve.28,29
Cognitive behavioral therapy (CBT) can also be initiated during the initial treatment or daily recording
months. At least three studies have demonstrated reduction in PMS symptom severity with CBT.30–32 Additionally, CBT added to the SSRI fluoxetine demonstrated
longer maintenance of treatment effects than fluoxetine
alone, but combining CBT and fluoxetine did not
confer added benefit in terms of degree of response or
rate of response.30 The disadvantage of CBT is cost, but
some practitioners offer CBT groups which are more
affordable than individual therapy, and the skills
acquired in CBT can also represent an important
investment in one’s own psychological well-being, as
the approach is non-pharmacological and is useful for
general stress reduction and coping with future adverse
life events.

PHARMACOLOGICAL MANAGEMENT
Combined oral contraceptives
Many reproductive women request contraception, and
hormonal contraception is the most commonly used
reversible method worldwide. Other potential noncontraceptive benefits of oral contraceptives (OCs) are
significant and include cycle regulation, reduction
development of anemia and functional ovarian cysts,
control of acne, decreased dysmenorrhea and pelvic
pain for those with early endometriosis, and risk reduction for ovarian and endometrial carcinoma. For those
women who also desire hormonal contraception, there
is now evidence that OCs can be beneficial for PMS
and PMDD; however, progestin-only methods have not
been reliably studied for this indication and currently
cannot be recommended.
Historically, OCs were not uniformly beneficial for
women with PMS, despite the elimination of ovulation,
but the higher doses of sex steroids in most of the
earlier generations of OCs may provoke more symptoms.33 The 7 days off active pills can also allow for
follicular development and a minicycle of exposure to
and withdrawal from endogenous steroids and residual
PMS-like symptoms in susceptible women.

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154 THE PREMENSTRUAL SYNDROMES

A newer OC, containing 20 or 30 ␮g of ethinyl estradiol ⫹ 3 mg of the progestin drospirenone, has demonstrated efficacy in the treatment of PMS and PMDD in
a number of recent studies.34–38 The antiandrogenic
and antimineralocorticoid effects of drospirenone, a
spironolactone derivative, combined with the ovulation
inhibition of an OC, may contribute to efficacy. The
drospirenone-containing 20 ␮g formulation provides a
24-day active/4-day placebo pill cycle, ensuring more
complete hormonal suppression.34,39,40 Shortening the
hormone-free interval from 7 to 4 or fewer days serves
to maintain sufficient circulating levels of exogenous
estrogen and progestin to inhibit follicular development and suppress ovarian steroid synthesis. In the
randomized controlled trials, nausea, headache, and
break-through bleeding are more prevalent in OC users
than in those assigned to placebo.

Psychopharmacology

Selective serotonin and serotonin/
norepinephrine reuptake inhibitors
For women with a formal diagnosis of severe PMS or
PMDD, but who do not desire hormonal therapy, have
residual symptoms on OCs, or have contraindications
for OCs, SSRIs are the treatment of choice. Many
placebo-controlled trials have demonstrated a 50–70%
response rate at standard daily SSRI doses, with significant improvement compared to placebo with all currently available SSRIs, including fluoxetine,41 sertraline,42
paroxetine,1 and citalopram,43 and the SNRI venlafaxine.44 The only three pharmacological agents currently
receiving a US Food and Drug Administration (FDA)
indication for PMDD are fluoxetine hydrochloride
(Sarafem), sertraline hydrochloride (Zoloft), and paroxetine hydrochloride (Paxil CR).
Before initiating SSRIs, prospective recording of
symptoms to ensure a symptom-free postmenstrual
phase is crucial (if the treating physician is not a psychiatrist) for many reasons. First, PMS necessitates
long-term treatment, potentially until menopause, since
it does not appear to go into remission as do depressive
disorders. A retrospective analysis of two previous clinical trials of fluoxetine in PMDD demonstrated that
symptoms recur within the first cycle after discontinuation. Secondly, it is important to rule out an underlying
affective disorder, in particular bipolar disorder, as
SSRIs can trigger a manic episode if prescribed without
a mood-stabilizing agent. Thirdly, luteal phase therapy
is effective for PMDD but not for depression. Finally, there
are parallels with the treatment of depression in pregnancy but this is a separate and specific consideration

and is individualized; reference to other texts is appropriate.45 Once the diagnosis of PMDD is well established and non-pharmacological approaches have failed,
any of the SSRIs can be tried.46 Fluoxetine has a recommended dose of 10–20 mg/day; in clinical studies,
significantly more side effects without increased efficacy were seen with 60 mg daily.40 Sertraline is initiated
at a dose of 25–50 mg/day and can be increased up to
150 mg/day for daily dosing; the average effective dose
is 100 mg/day. Paroxetine CR is initiated at a dose of
12.5 mg/day and can be increased to 25 mg/day.
Citalopram is dosed at 20 mg/day.
Unlike the treatment of affective disorders, in which
a clinical response requires 3–6 weeks of exposure to
an SSRI, the response in PMS/PMDD patients occurs
within the first days of exposure. The shorter response
interval (1–2 days) in premenstrual disorders is the
basis of intermittent treatment with SSRIs during the
luteal phase, which has also proven effective in many
studies and is the preferred mode of SSRI administration for PMDD or severe PMS without comorbid affective or anxiety disorders.43,47,48 In severe PMS/PMDD
patients, a randomized controlled trial of continuous vs
intermittent dosing with sertraline at 50–100 mg/day
for three cycles showed significant improvement in mood
and physical symptoms in both groups of treated patients
during the first month of treatment.49 Luteal phase
dosing begins on about day 14 or just after presumed
time of ovulation, and continues until the onset of
menses. Fluoxetine 20 mg/day, sertraline 50–100 mg/day,
paroxetine CR 12.5–25 mg/day, and citalopram 20 mg/
day can be initiated in this fashion More recently, intermittent, weekly luteal phase dosing of enteric-coated
fluoxetine in 90 mg doses (two doses) was shown to be
efficacious and well-tolerated.50 Symptom-onset dosing
with a newer SSRI, escitalopram (Lexapro), has been
compared to luteal phase dosing with the same drug in
PMDD patients. Although both dosing strategies resulted in significantly improved daily symptom reporting
scores, women with more severe PMDD were less likely
to improve with symptom-onset dosing.51 Aside from
equal, if not improved, effectiveness and compliance in
luteal phase dosing, another clear advantage is the lack
of discontinuation symptoms with the intermittent
dosing52 and possibly fewer side effects such as weight
gain and sexual dysfunction.
In addition to improvement in mood, other aspects
of PMS and PMDD are often relieved by treatment
with SSRIs. At the higher dosing interval, SSRIs reduce
the most common physical symptoms, such as bloating
and breast tenderness, associated with PMDD.40
However, intermittent luteal phase dosing of sertraline
failed to demonstrate significant improvement in physical symptoms, but did effectively reduce complaints of

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premenstrual cognitive disturbance, increased appetite,
increased sleep, and lethargy.48 Paroxetine CR resulted
in significant improvement compared to placebo in
mood symptoms at 12.5 mg daily dosing, but physical
symptom reduction required 25 mg daily dosing.53
Fluoxetine reduced symptoms that negatively impact
work capacity within the first cycle of treatment.54
If initial exposure to one of the SSRIs proves problematic due to side effects or lack of efficacy, another
SSRI should be utilized. Common side effects can be
found in Table 17.4.55,56 Switching to another SSRI
involves discontinuing the first drug quickly while the
newer drug is titrated to an effective dose. If withdrawal effects from the first medication result, its discontinuation should be done more gradually. In the
case of luteal dosing, the new drug can be started with
the next menstrual cycle.
SSRIs should be taken in the morning, unless sedation results, in which case the dose can be taken in the
late afternoon, generally before 4 pm to prevent insomnia. Gastrointestinal side effects and headache are
usually transient; weight gain can also occur.57 All
SSRIs can be associated with lowered libido and delayed
orgasm or anorgasmia.58 Besides lowering dose or duration of therapy, antidotes include dopaminergic agents,
such as bupropion; adrenergic agents such as Ritalin
(methylphenidate); buspirone; and phosphodiesterase
inhibitors like sildenafil.58
When the possibility of becoming pregnant exists,
certain SSRIs might be preferred to others. As the
PMDD will disappear with pregnancy, therapy will not
be required. If the woman has underlying depression
and requires treatment, known risks of SSRI therapy59
warrant individualized care.
Discontinuation symptoms should also be considered in the choice of continuous, non-luteal dosing of
SSRI, as symptoms vary considerably depending upon
the drug and dosing schedule. Paroxetine has the most

Table 17.4 Common side effects of daily SSRIs
with an FDA indication for PMDD55
Side effect

Fluoxetine

Sertraline

Paroxetine

Anxiety
Sedation
Insomnia
Nausea
Decreased
libido
Weight gain

+++
+
++++
++++
+

+
++
++++
++++
+

+
++++
++++
++++
+

0/+

+

++

significant withdrawal effects and is therefore weaned
slowly, tapering by half the dose every several days
until discontinued completely. The taper can be lengthened if symptoms occur. Sertraline should also be
weaned slowly. Because of its long half-life, fluoxetine
at 20 mg daily can be stopped without a taper. Escitalopram and citalopram should be tapered, but this can be
done fairly rapidly.
If a woman conceives while using an SSRI and continues treatment, there are risks60 of neonatal syndrome
at birth. Hence, treatment should be discontinued or a
psychiatric opinion should be sought if it is thought
that her condition is so severe that further psychotropic
therapy is required.

Anxiolytics
Other classes of psychotropic medications with some
efficacy for luteal phase dosing only include buspirone
(5HT1A agonist), 10 mg 2–3 times per day, and alprazolam (GABAA agonist), 0.25–0.5 mg taken 2–3 times
per day. Although these agents have shown only
minimal or modest usefulness for PMS/PMDD compared to SSRIs, their intake results in fewer sexual side
effects.52,61 These agents or other anxiolytics can also
be added (in the luteal phase only, in order to preclude
development of tolerance and addiction) to SSRIs if
anxiety persists while taking an SSRI.

Diuretics
Specific physical symptoms that are most troubling to
the patient may need to be addressed separately. For
example, in women with severe mastalgia and bloating,
use of spironolactone, an aldosterone receptor antagonist, may be a helpful adjunct. A dose of 100 mg from
day 12 of the cycle to the onset of menses relieved PMS
symptoms in a placebo-controlled trial, and by cycle
three, with significant improvement in abdominal
bloating, swelling of extremities, breast discomfort,
and even mood symptoms of irritability, depression,
anxiety, and tension.62–64

Gonadotropin-releasing hormone agonists
The use of a GnRH agonist to suppress ovarian sex
steroids provides symptomatic relief in the majority of
women with PMS;65–68 however, long-term studies are
lacking. Bone density, and cardiovascular and vaginal
health can theoretically be maintained and vasomotor
symptoms prevented with a menopausal dose of continuous estrogen/progestin or tibilone as hormone addback therapy.69 A GnRH analogue, even with hormone
add-back therapy, remains a third-line therapy if

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156 THE PREMENSTRUAL SYNDROMES

psychotropics have failed or if there is a concurrent
gynecological indication for its use, such as severe
cyclic pelvic pain or endometriosis or prior to contemplating oophorectomy for severe symptoms. GnRH
analogues can also be employed to help determine if
severe premenstrual symptoms in women with an
underlying mood disorder are related to PMDD or the
primary mood disorder. Side effects of GnRH analogues include myalgias, arthralgias, headaches, and
residual vasomotor symptoms if the doses of add-back
hormone therapy are insufficient.

Danazol
Danazol is another option for women who also have
endometriosis, or just bothersome dysmenorrhea, but
who do not require contraception, or for whom estrogen is contraindicated. Danazol, however, is an androgen analogue and side effects can include weight gain,
acne, hirsutism, and decreased breast size.70,71 Many
women will ovulate with the daily 400 mg dose; therefore, contraception is imperative in sexually active
patients, as danazol can virilize the developing fetus.

Progesterone
Progesterone was evaluated in a systematic review of
319 women72 and found to produce minimal improvement in PMS symptoms over that of placebo significantly eased PMS symptoms to a greater degree than
placebo, but other individual studies have not demonstrated superior efficacy of suppositories or oral micronized progesterone, and side effects include nausea,
breast pain and uterine bleeding irregularities.

Estradiol
Transdermal estradiol (200 ␮g) has demonstrated efficacy in controlling PMS symptoms if the dose is high
enough to inhibit ovulation;73 however, the endometrium must be protected with progestin. In the aforementioned study, norethindrone 5 mg/day from days 19
to 26 was administered.73 As progestins can recreate
PMS symptoms, an intrauterine device containing a
‘progestin’ is preferable. Skin patches are associated with
skin irritation in some women. If estradiol subcutaneous
implants are used, similar efficacy can be achieved and,
while this avoids the use of the patch, it will require a
simple insertion of the implant under local anesthetic.
The restimulation of symptoms by the oral progestagen can be avoided by using an intrauterine device
containing levonorgestrel (levenorgestrel-releasing intrauterine system; LNG IUS). This protects the endometrium while keeping blood levels (and therefore CNS

levels) or progestogen low. Although there is evidence
that estradiol is effective in treating PMS symptoms and
the LNG IUS prevents or even reverses endometrial
hyperplasia, there are no published data to confirm the
efficacy of the combination. There is a great deal of
anecdotal evidence from UK clinical practice.

Tibolone
Tibolone is a synthetic steroid with estrogenic, androgenic, and progestogenic properties, with many studies
demonstrating efficacy for menopausal symptoms but
with some evidence for 2.5 mg daily (one small
randomized placebo-controlled cross-over trial of 18
ovulatory women) for the treatment of PMS.74 Significantly improved scores, as documented by the VAS,
were noted in the 2nd and 3rd month of a 3-month
trial. Recommendations concerning this compound
await further confirmatory trials, although it is particularly useful as add-back therapy during the use of
GnRH therapy.

COMPLEMENTARY AND ALTERNATIVE
THERAPIES
Several complementary and alternative medicine
approaches have demonstrated some efficacy, but also
mixed results, in premenstrual disorders, and studies
were small and some not well-controlled.75 These include
bright light therapy, certain herbal and nutritional supplements, the use of exercise, and various mind–body
approaches.21,76,77 L-Tryptophan, a serotonin precursor, given at a dose of 6 g/day, was significantly more
effective than placebo in the control of extreme mood
swings, dysphoria, irritability, and tension in patients
with PMDD.78 Vitamin B6 was mentioned previously.25
Chaste tree extracts (Vitex agnus-castus) are widely
used to treat premenstrual symptoms, particularly
mastalgia, with few reported side effects.79,80

SURGICAL OPTIONS
Hysterectomy with bilateral salpingo-oophrectomy is
effective for severe PMS/PMDD81,82 and can be proposed for women in their 40s who have completed
childbearing and have failed other therapies or who are
planning a hysterectomy for other gynecological indications. Oophorectomy before age 60 years old is theoretically associated with increased cardiovascular
mortality,83 and estrogen replacement should be administered. Hysterectomy alone is not effective for relief of

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PMS, and bilateral oophorectomy alone requires both
progestin and estrogen replacement with the risk of
re-stimulating.

CONCLUSION

9.

10.

11.
12.

Premenstrual syndrome and premenstrual dysphoric
disorder are common and often disabling conditions
affecting reproductive-aged women. A formal diagnosis should be sought whenever premenstrual symptoms
are described. Underlying medical, psychiatric, and
psychosocial conditions should be excluded, and the
premenstrual timing and postmenstrual relief of the
symptoms documented prospectively by nightly recording for at least two cycles. Once a definitive diagnosis is
made, initiation of various treatment strategies can be
effective in alleviating symptoms. Education, lifestyle
change, cognitive behavioral therapy, calcium supplementation, certain hormonal oral contraceptive preparations, and the diuretic spironolactone can be
effective. The administration of a serotonergic antidepressant is likely to alleviate symptoms and improve
significantly the quality of life and functional status.
Luteal phase dosing is the preferred method of treatment with SSRIs in many cases, as discontinuation
symptoms and overall side effects are minimized. The
use of GnRH analogues and estradiol patches and
implants should be reserved for the most severe cases.

INTRODUCTION
Males and females differ in their predisposition to
certain clinical disorders. One of the most widely documented findings in psychiatric epidemiology is that
women have higher rates of major depressive episodes
than men, a phenomenon observed worldwide using a
variety of diagnostic schemes and interview methods.1,2
The prevalence of depression among women in these
studies was reported to be between 1.5 and 3 times that
of men. Although a genetic predisposition to major
depression has been extensively postulated, the actual
mechanisms involved in this disorder are still being
investigated. Several authors have reported similarities
and associations between the symptoms of affective
disorders such as anxiety, panic disorder, major depression, and seasonal affective disorder, and premenstrual
syndrome/premenstrual dysphoric disorder (PMS/
PMDD).3–8 It has also been noted that the incidence of
anxiety, mood disorders, and depression among women
suffering with PMS is greater than that of the general
population.9–11
Evidence supporting the view that a genetically determined vulnerability plays a major role in the expression
of PMS/PMDD is derived from twin and family
studies,12–15 that showed a high correlation between
mothers and daughters and also between mono- and
dizygotic twins. Additionally, a similarity of PMS subtypes was noted between mothers and daughters. Thus,
genetic factors have been implicated repeatedly in the
pathogenesis of PMS/PMDD, although no specific susceptibility gene has been identified.

PMDD AND BRAIN NEUROTRANSMITTERS
We have seen in earlier chaperts (Chapter 10) that the
definitive cause of PMS is unknown but it appears to be
directly related to the ovarian cycle trigger. The concept

of a hormonal imbalance has been popular, but there is
no supportive evidence. The hormone status of PMS
patients does not appear to differ from that of asymptomatic women.16–21
Several lines of evidence suggest that an underlying dysregulation of serotonergic neurotransmission
plays a pivotal role in PMDD.22–32 Data from both
animal and clinical studies indicate that (serotonin; 5hydroxytryptamine, 5-HT) exerts an inhibitory effect
on symptoms such as irritability, affect lability, and
depression, which are core features of premenstrual
dysphoria.33,34 Ovarian steroids have been shown to
profoundly influence the activity of the serotonergic
system.35–37 In the central nervous system (CNS), there
is evidence of region-specific effects on serotonin synthesis, turnover, uptake, and release, and on specific
receptors by estradiol and progesterone.38,39 Falling
levels of ovarian hormones (e.g. in the late-luteal phase
of the menstrual cycle) have been associated with
decreased serotonergic activity.40
Low serotonin levels in red blood cells and
platelets27–29,41 have been demonstrated in PMS patients
compared with controls. This serotonin deficiency has
been proposed to enhance CNS sensitivity to normal
progesterone following ovulation.42 Further credence
to the potential involvement of serotonin in the pathogenesis of premenstrual dysphoria is provided by the
effectiveness of selective serotonin reuptake inhibitors
(SSRIs) such as fluoxetine and sertraline43 in the treatment of severe PMS/PMDD. Vitamin B6 (pyridoxine)
is a cofactor in the final step in the synthesis of serotonin and dopamine from tryptophan. No data have
yet demonstrated consistent abnormalities of either
brain amine synthesis or deficiency of cofactors such as
vitamin B6 in PMDD.44
There is also increasing support for the hypothesis
that ovarian hormones modulate ␥-aminobutyric acid
(GABA) neuronal function. GABA is the primary
inhibitory neurotransmitter in the CNS. Disorders in

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162 THE PREMENSTRUAL SYNDROMES

GABAergic neurotransmission have been linked
to epilepsy, anxiety disorders, schizophrenia, and
PMDD.45,46 Plasma and cortical GABA levels of women
with PMDD have been demonstrated to be lower during
the late-luteal phase of the menstrual cycle, compared
with the mid-follicular phase.45–48 Data from animal
studies suggest that the GABAergic system is substantially modulated by menstrual cycle phase.49 This raises
the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids
as potentially important contributors to the pathogenesis of PMDD.50,51
Moreover, progesterone is converted to neuroactive
steroids (5␣-pregnane steroids) in the brain. Progesterone
metabolites (allopregnanolone and pregnanolone) appear
to have anxiolytic and hypnotic properties via GABA
type A (GABA-A) agonistic activity. Therefore, dysfunction in the GABA-A/neurosteroid system has been
implicated in the pathogenesis of mood disorders and
premenstrual syndrome.42,52 Diminished levels of luteal
phase ␤-endorphin have been shown in women with
PMS/PMDD compared with asymptomatic controls.53–55
Symptoms such as anxiety, food craving, and physical
discomfort have been associated with a significant
premenstrual decline in ␤-endorphin levels.56–58 Other
neurotransmitters may have relevance to PMDD, for
example dopamine and acetylcholine, although the evidence for these is less convincing.
If the above suppositions are substantiated, it would
seem that PMDD is not caused by an endocrine imbalance per se, but rather from an increased sensitivity
to normal circulating level of ovarian hormones, particularly progesterone, secondary to a neuroendocrine
disturbance.

THE SEROTONERGIC PATHWAY
As a result of the impressive therapeutic effects of SSRIs
in up to 60–70% of women with PMS/PMDD, dysregulation of serotonin neurotransmission is a popular
hypothesis in the pathogenesis of premenstrual dysphoria. Serotonin is a monoamine neurotransmitter stored
at several sites in the body. The majority (95%) is
located in the enterochromaffin cells of the intestinal
mucosa. Smaller amounts occur in platelets and in
the CNS, where the highest concentrations are found
in the raphe nuclei of the brainstem. Serotonergic
neurons project from the raphe nuclei to various brain
regions, and play a vital role in modulating emotion,
motor function, and cognition, as well as circadian and
neuroendocrine functions such as appetite, sleep, and
sexual activity. Serotonin is synthesized from the amino
acid tryptophan, a reaction catalyzed by tryptophan

hydroxylase (TPH), and is stored in presynaptic vesicles until required. Upon neuronal firing, serotonin is
released extracellularly and binds to postsynaptic
receptor proteins, thereby transmitting a signal from
one cell to the next (Figure 18.1). It also binds to presynaptic autoreceptors (5-HT1A and 5-HT1B/D), which
regulate further serotonin release. Synaptic serotonin
concentration is directly controlled by its rapid reuptake
into the presynaptic terminal by a specific transporter
protein (5-hydroxytryptamine transporter, 5-HTT).
Serotonin uptake in platelets occurs by a similar active
transport process.59 Furthermore, the amino acid
sequences of the two transporter proteins are identical
and are encoded by the same gene.60,61 Monoamine
oxidase A (MAOA) catalyzes the catabolism of serotonin to 5-hydroxyindoleacetic acid (5-HIAA) and is
pivotal in the regulation of intracellular serotonin levels
(Figure 18.2).
PMDD and psychiatric disorders share several key
symptoms, such as anxiety, depression, tension, and
affective lability.3,6–8 In light of this association, and the
myriad of publications linking serotonergic polymorphisms to depressive disorders, the lack of reported
genetic studies in PMDD is surprising. Below, we
describe potential candidate gene polymorphisms suitable for study in PMDD, and include relevant evidence
from numerous psychiatric studies.

GENETICS OF THE SEROTONERGIC
SYSTEM IN PMDD
The concept of genetic polymorphisms
The fundamental basis of genetic polymorphism in a
population is variation of the nucleotide sequence of
DNA at homologous locations in the genome. These
differences in sequence can result from mutations
involving a single nucleotide or from deletions or insertions of variable numbers of contiguous nucleotides. At
many loci within the human genome, two or more
alleles may occur with significant frequency in the same
population. These loci are said to be polymorphic. Their
existence allows for multiple combinations of alleles at
different loci, and is responsible for both the incredible
diversity in populations and the uniqueness of individuals. However, this very diversity is also thought to
account for genetic susceptibility to many diseases. Thus,
the study of polymorphisms in key candidate genes is a
potentially powerful tool in the investigation of complex
polygenic diseases, in which multiple genes (each of which
may have a relatively minor effect) and environmental
factors collaborate to cause disease. Applying this
concept to PMDD, polymorphisms of genes controlling

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Presynaptic neuron
Presynaptic
receptors
1A
Tryptophan

TPH

MAO
5-HT

5HIAA

1B

Serotonin
transporter
(5-HTT)

SSRI
Synapse

1A

Postsynaptic
receptors
2A

2C

Postsynaptic neuron

Figure 18.1 Schematic diagram of 5-HT metabolism.

NH2

NH2

NH2

OH

OH
HO
O
Tryptophan
hydroxylase

N
H

N
H

HO
O
Aromatic amino
acid decarboxylase

5-Hydroxytryptophan

Tryptophan

5-Hydroxytryptamine
B6

NH2

HO

O

OH

HO

N
H

Monoamine
oxidase A

5-Hydroxytryptamine

Figure 18.2 Serotonin (5-HT) synthesis and catabolism.

N
H

N
H
5-Hydroxyindoleacetic acid

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164 THE PREMENSTRUAL SYNDROMES

the serotonin or other neurotransmitter pathways may
influence susceptibility, with cyclical ovarian hormone
fluctuations providing the environmental trigger.
Allelic variants can occur anywhere in the genome:
some are found within exons, which are the coding
regions of genes, whereas others are located in introns,
promoter regions, or sites that are not closely linked to
any known expressed gene.62

Types of genetic polymorphisms
Single-nucleotide polymorphisms (SNPs) are allelic
variants that have been generated as the result of conversion of one nucleotide to another at a homologous
position. When present within a coding region (exon)
of a gene, the expressed product may or may not have
a single amino acid difference, depending on the resulting codon change. In some cases, the resulting codon
stops the transcription process and results in the production of a truncated peptide. SNPs that are located in
regulatory regions of an expressed gene can alter the
transcription efficiency of that gene but not the protein
sequence.62 Some polymorphisms coincide with the
target nucleotide sequences recognized by restriction
enzymes. Polymorphisms that occur at restriction enzyme
sites are known as restriction fragment length polymorphisms (RFLPs). RFLPs are extremely useful because
they can be used to identify genetic markers.63 Deletion
or insertion mutants have also been found in functional
genes. The consequence of a deletion depends on its
precise location: whether it produces a mutation that
results in an alteration in the reading frame of the gene
and the function of the expressed product.
Other types of allelic variance in association with a
particular gene are repetitive sequence elements which
are arranged in tandem. Depending on the repeat unit
length and the degree of repetition per locus, these repetitive sequence elements are known as satellite, minisatellite and microsatellite. Polymorphisms created by
such elements are termed variable number of tandem
repeats (VNTR) polymorphisms.63
Below, we describe potential candidate gene polymorphisms suitable for study in PMDD, and include
relevant evidence from numerous psychiatric studies.

Candidate genes in the
serotonergic pathway

Tryptophan hydroxylase
TPH catalyzes the rate-limiting step in serotonin synthesis, and is one of the most important regulators of
the serotonergic system. In humans, two different TPH
genes exist, which encode two enzymes (TPH1 and

TPH2), with an overall sequence homology of 71%.64
TPH1 is expressed in peripheral tissues and in the
pineal body, whereas TPH2 appears to be responsible
for serotonin synthesis in the rest of the brain. Since the
existence of TPH2 is a relatively recent discovery
(2003), most studies conducted to date have focused on
TPH1 markers. Numerous TPH1 sequence variants
have been reported.65 Of these, the most commonly
studied are the two promoter polymorphisms G-6526A
and G-5806T, and the two markers A218C and A779C
in intron 7. It has been suggested that sequence variations within the promoter region may modify TPH1
expression and affect serotonin synthesis, and this has
been supported by successive deletion analysis of the
promoter region, which led to a decrease in promoter
activity.66 The A218C marker has been studied extensively in psychiatric disorders.67 The exact mechanism
linking the A218C polymorphism to reduced expression of the gene product remains unknown; however,
the functional relevance of this polymorphism has
been demonstrated for a series of clinical syndromes
(e.g. bipolar disorder, suicide attempts, and suicidal
behavior).68–74 The A allele has been associated with
decreased serotonin synthesis75 and slower response to
SSRIs76,77 in subjects with major depressive disorders.
Numerous studies have attempted to link TPH1 polymorphisms with a variety of mood disorders, but have
given conflicting data.78–81 In a recent study, we found
no significant associations between PMDD and the
G-6526A, G-5806T, or the A218C polymorphisms of
the TPH1 gene.82 Until recently, TPH1 was believed to
be the sole rate-limiting enzyme for neuronal serotonin
synthesis, which occurs in the raphe nuclei of the brainstem. This lack of association is not surprising in the
light of the discovery of a second tryptophan hydroxylase (TPH2) isoform,64 which is expressed predominantly
in the brainstem but not in peripheral tissues.83,84
Initial reports of TPH2 polymorphisms indicate an
association between several SNPs and major depression.85–87 Thus, TPH2 may be a strong candidate gene
for future study in PMDD.

The serotonin transporter
The serotonin transporter (5-HTT) protein is the
primary mechanism for removing serotonin from the
synaptic cleft. Three common 5-HTT polymorphisms
have been studied in psychiatric disorders: 5-HTT LPR,
VNTR-2, and 3⬘UTR G/T. The 5-HTT LPR is a 44
nucleotide insertion/deletion in the promoter region
giving rise to long (L) or short (S) alleles.88 This polymorphism has been evaluated in several studies. Infants
with the short homozygous (S/S) 5-HTT LPR genotype
had higher scores on negative emotionality and distress

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than infants with the L/S or L/L genotypes.89 The
5-HTT LPR was also strongly associated with childhood aggression.90 Homozygosity for the short variant
of the 5-HTT LPR polymorphism was shown to be significantly more frequent in bipolar patients than in
controls.73 Courtet and associates74 reported a significant association between the 5-HTT LPR S/S genotype
and further suicide attempts among patients who had
previously attempted suicide. The S allele was also
more likely to have higher symptom counts for aggressivity, attention deficit, and conduct disorders in males.
However, among females, the short variant (S/S, L/S)
was associated with lower levels of such behavior.91
The S variant has been shown in vitro to be less transcriptionally active than the L allele, resulting in decreased
5-HTT expression and uptake,92 and a poorer response
to SSRI therapy in Caucasian subjects with mood
disorders.93,94
The 5-HTT VNTR-2 polymorphism comprises 9,
10, or 12 copies of a 17 base pair repeat element in
intron 2.95 This polymorphism has been suggested to
regulate transcriptional activity of the 5-HTT gene, and
the 12-repeat allele has been associated with increased
5-HTT expression, compared with the 9- and 10-repeat
variants.95,96 Using an ethnically homogeneous sample
of highly aggressive Caucasian children and their
matched controls, Beitchman and colleagues97 reported
an association of this polymorphism with aggression. It
has also been suggested that 5-HTT VNTR-2 influences
age of onset in patients with bipolar affective disorder.72
Moreover, a recent meta-analysis of 12 populationbased association studies consisting of 2177 cases and
2369 control subjects showed a highly significant association between the 5-HTT VNTR-2 polymorphism
and schizophrenia.98 The 3⬘UTR G/T is an SNP located
in a putative polyadenylation site of the 3'untranslated
region of the 5-HTT gene.99 This polymorphism has
been linked with bipolar and attention deficit hyperactivity disorders.100,101
To date, studies of these three 5-HTT polymorphisms in PMDD have found no significant differences
in genotype distribution between healthy controls and
PMDD subjects in any of the markers.102,103

Monoamine oxidase A
MAOA is a mitochondrial enzyme that catalyzes the
oxidative deamination of neurotransmitters such as
dopamine, norepinephrine, and serotonin. Increased
MAOA activity might feasibly be expected to contribute
to the pathogenesis of conditions associated with reduced
serotonergic neurotransmission, such as PMDD. Several
different polymorphisms in the MAOA gene have been
identified: of these, the VNTR-1 and the Fnu 4H1

RFLP are of particular interest. Transcriptional activity
of the human MAOA gene is modulated by the VNTR1 polymorphism. Based on functional characterization,
alleles with 3.5 or 4 copies of the repeat sequence are
transcribed 2–10 times more efficiently than those with
3 or 5 copies of the repeat.104,105 The presence of an
Fnu 4H1 restriction site in exon 8 (the G allele) has
been associated with a high MAOA activity in healthy
individuals.106 MAOA gene polymorphisms have been
linked to the pathogenesis of major depression, associated with insomnia in depressed individuals, attention
deficit hyperactivity disorder, alcoholism and binge
drinking.106–109
Our collaborative group has recently studied the
association between the VNTR-1 and Fnu 4H1 polymorphisms and PMDD.103 We found no significant distribution pattern associated with the high-activity
alleles 3.5 and 4, or the lower-activity alleles 4 and 5 in
the VNTR-1 in our cases and controls. Although the
G/T genotype in the Fnu 4H1 RFLP was more common
in the PMDD group than in the controls, this difference
was not statistically significant, and the overall frequency of the G and T alleles was similar in both
cohorts.103

Serotonin receptors
Over the past decade, more than 14 different serotonin
receptors have been cloned through molecular biological techniques. There are seven classes of serotonin
receptors. Some of these are divided into several
subclasses based on structural and operational characteristics (e.g. 5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F,
5HT2A, 5HT2B, and 5HT2C).
The proposed mechanisms by which gonadal hormones influence neurotransmitters, in general, and
serotonin, in particular, are not only achieved by affecting their rate of production and catabolism but also by
modulating their individual receptor’s function and
responsivity. For example, it has been shown that estrogen increases serotonin (5-HT) postsynaptic responsivity, up-regulates 5-HT1 receptors, and down-regulates
5-HT2 receptors.110,111 Research investigating vulnerability to anxiety and irritability indicated that agonists
of 5-HT1A receptor and antagonists of the activating
5-HT2 receptor decrease anxiety.112–114 Moreover, the
5-HT1A receptor is expressed as a postsynaptic receptor,
in addition to being the major presynaptic autoreceptor
on serotonergic raphe neurons.114 The electrophysiological activity of serotonergic neurons is regulated,
at least in part, through a negative feedback mechanism triggered by the stimulation of presynaptic
5-HT1A autoreceptors. This receptor activity has also
been linked to responsiveness to SSRI therapy in some

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166 THE PREMENSTRUAL SYNDROMES

psychiatric disorders. An initial delayed response to
SSRIs is thought to be secondary to activation of the
5-HT1A autoreceptors, as a result of the immediate
increase in extracellular serotonin at the somatodendritic level following treatment initiation.114 Therefore,
the associations between serotonergic receptor gene
polymorphisms, PMDD, and response to SSRIs therapy
are undoubtedly interesting areas for future research.

CONSIDERATIONS FOR GENETIC
STUDIES IN PMDD
If genetic studies of PMDD are to be conducted, it is
absolutely vital that participants are diagnosed correctly
so that the description of the phenotype is precise. The
importance of clinical categorization using strict inclusion and exclusion criteria cannot be overemphasized.
Before completing any prospective rating, it is essential
to ensure that potential participants are not taking any
hormonal contraceptives or replacement therapy both
during the monitored cycles and for a minimum of
2 months previously. Women should be excluded if
they are pregnant, planning a pregnancy, have an existing or past history of psychiatric disorder, or are taking
psychotropic medications. Diagnosis of PMDD can
present significant challenges, owing to the subjective
nature of symptom interpretation and reporting. Medical
researchers and clinicians offer conflicting opinions
about whether PMDD and its milder variant, PMS, are
synonymous or separate diagnoses115 (see Chapter 2).
Gonadal hormonal influences on the brain processes
involved in regulation of mood, behavior, and cognitive
functions are complex and are not limited to the serotonergic system, but also involve other major
neurotransmitter pathways such as the noradrenergic,
dopaminergic, acetyl cholinergic, and GABAergic
systems. There is increasing support for the hypothesis
that gonadal steroids involved in the regulation of the
human menstrual cycle modulate GABA neuronal function. Moreover, several polymorphisms in genes controlling the GABAergic system have been linked to mental
health and substance misuse problems.116–120 Hence,
genes regulating the GABAergic system are potentially
strong candidates to be investigated for any association
with PMDD.

The polygenic approach
At present, there are a significant number of genetic
markers that can be used in genetic association studies
of PMDD. Although each polymorphism can be studied
in isolation, it is much more informative to analyze
a panel of putative markers in a region of interest. The

combination of marker alleles on a single chromosome
is called a haplotype. For haplotypes which include
markers tightly linked with each other (such as those
within the same gene), alleles often display statistical
dependence, a phenomenon called linkage dysequilibrium (LD), or allelic association. One major aspect of
haplotype analysis is to identify LD patterns in different regions and different populations, since the very
existence of LD among markers makes it possible to
localize genetic variants underlying complex traits.46
When multiple markers associated with a specific chromosomal region are studied to assess the association
between this region and traits of interest, a statistical
analysis based on haplotypes may be more meaningful
than separate analyses of each individual marker. This
has been demonstrated by both simulation and empirical studies.46

CONCLUSION
Individual hypersensitivity to physiological hormonal
fluctuations that occur during periods of hormonal
change such as the menstrual cycle, postpartum, and
the perimenopause contributes to the vulnerability to
PMS, PMDD, postpartum, and perimenopausal behavioral disorders. Family and twin studies have shown that
this hypersensitivity has a genetically determined component. However, the assumption that PMS/PMDD
results from an isolated neurotransmitter disorder is
probably too simplistic, and an imbalance or disturbed
feedback mechanisms between several transmitter
systems or disturbed feedback between several components and stages within the same system is a more plausible hypothesis.

GLOSSARY OF TERMS
(Adapted from the National Human Genome Research
Institute: www.genome.gov)
Allele: one of the variant forms of a gene at a particular
locus.
Exon: a nucleotide sequence in DNA that carries the
code for the final messenger RNA molecule and thus
defines a protein’s amino acid sequence.
Gene: the functional and physical unit of heredity
passed from parent to offspring.
Genotype: the genetic identity of an individual that
does not show as outward characteristics.
Intron: a non-coding region of DNA that is originally copied into RNA but is cut out of the final RNA
transcript.

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Linkage: the association of genes and/or markers that
lie near each other on a chromosome. Linked genes and
markers tend to be inherited together.
Locus: the place on a chromosome where a specific
gene is located (plural: loci).
Nucleotide: one of the structural components of DNA
and RNA, consisting of a base (guanine, thymine,
adenine, or cytosine) plus a molecule of sugar and a
molecule of phosphoric acid.
PCR (polymerase chain reaction): a fast, inexpensive
technique for making an unlimited number of copies of
any piece of DNA.
Phenotype: the observable traits or characteristics of an
organism, such as hair color, weight, or presence or
absence of disease.
Polymorphism: a common variant in the sequence of
DNA among individuals.
Promoter: the part of a gene that contains the information to turn the gene on or off. The process of transcription is initiated at the promoter.
RFLP (restriction fragment length polymorphisms):
genetic variations at a site where a restriction enzyme
cuts a piece of DNA. Such variations affect the size of
the resulting fragments.
SNP (single nucleotide polymorphism): common, single
nucleotide variations that occur in human DNA at a
frequency of one every 1000 bases.
Transcription: the process through which a DNA
sequence is copied to produce a complementary RNA;
i.e. the transfer of information from DNA to RNA.
VNTR: short repeated segments of identical DNA at a
particular locus in the human genome. This number of
repeated units varies between individuals.

INTRODUCTION
Premenstrual dysphoric disorder (PMDD) represents
an affective syndrome, the symptoms of which are confined to the luteal phase of the menstrual cycle and are
of sufficient severity to interfere with normal life activities. PMDD causes substantial suffering to the approximately 5–10% of women of reproductive age with this
disorder. The degree of functional impairment is at
least equivalent to that seen with dysthymia (i.e. chronic
depression) and, in some aspects (e.g. social/leisure and
parental impairment) is equivalent to chronic or recurrent major depression. Given the prevalence of PMDD
(almost four million women), the years at risk, and an
average of 6 days of severe symptoms per cycle, the
World Health Organization’s model calculates the
burden of PMDD in the United States alone as 14.5
million disability adjusted life years. Two forms of
treatment have demonstrated efficacy in PMDD (i.e.
selective serotonin reuptake inhibitors [SSRI] and
ovarian suppression); however, neither treatment is effective
in all women with PMDD, and predictors of response
to either treatment are not known, nor are the mechanisms of their therapeutic actions.
The timing of symptoms of PMDD both distinguishes this condition and leads to speculation about its
underlying pathophysiology. Since the menstrual cycle
is a series of hormonal events involving endocrine
activity at the hypothalamus, pituitary, and ovary, it
was presumed that the symptoms of PMDD must result
from abnormal levels of some ovarian or menstrual
cycle-dependent factor, much in the way that depression may result from other endocrinopathies involving
thyroid or adrenal dysfunction. Studies reviewed in
previous chapters in this textbook, however, have overwhelmingly, refuted the presumption that circulating

gonadal steroid levels are abnormal in women with
PMDD. Thus, traditional hormone deficiency-based
models of behavioral regulation do not provide adequate explanations for PMDD. Speculation about the
pathophysiology of PMDD may be informed by those
characteristics of women with this disorder that are
consistently demonstrated in the literature: evidence of
altered serotonergic system function in women with
PMDD compared with controls, the therapeutic efficacy of SSRIs but not other antidepressants, and the
provocation of PMDD symptoms by physiological
levels of ovarian steroids. Nonetheless, to propose that
PMDD simply reflects an interaction between a hormonal signal and an abnormality of neurotransmitters
(e.g. serotonergic dysfunction) is not adequate, since
neither the nature of the signal nor the nature of the
neurotransmitter abnormality is understood. Moreover, there are several characteristics of PMDD that
need to be included in efforts to develop a disease
model for PMDD. First, PMDD involves symptoms of
both affective dysregulation and cognitive disturbance
and, therefore, it is in large part a brain disease. Thus,
in addition to understanding the nature of the hormonal signal, the brain regions targeted by this signal and
the relevant neurocircuitry of PMDD need to be identified. Finally, an appropriate disease model for PMDD
must not only account for the timing of the symptoms
during the luteal phase but also their emergence with
time (appearing commonly in the late 20s or 30s) and
their minimal expression in most women (only 5–10%
of women have PMDD). An attempt to model these
characteristics not only results in a reconceptualization
of PMDD that will generate new hypotheses to be
examined but also permits the development of theoretically derived and evidence-based treatment strategies
for this condition.

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In this chapter we first provide a brief summary of
the data that we believe provide directions for the design
of future investigations into the pathophysiology of this
condition. Next, we discuss several hormonal mechanisms and physiological substrates that potentially are
involved in the development of PMDD. Specifically, we
focus on the nature of the hormonal signal or trigger
for symptom occurrence, the substrates that are implicated in the symptoms of PMDD (i.e. brain regions and
connections, hypothalamic–pituitary–adrenal [HPA]
axis), and finally, the mechanisms whereby a hormonal
signal could be differentially modulated to alter stress
responsivity and produce affective, cognitive, and behavioral symptoms in a subgroup of women.

BACKGROUND
Once investigators had agreed on the appropriate
methods for sample selection in studies of PMDD, they
were then able to reasonably attempt to test hypotheses
about physiological disturbances accompanying PMDD.
Several studies documented that there were no differences in plasma levels of gonadotropins or gonadal
steroids in women with prospectively confirmed PMDD
compared with controls in whom the absence of premenstrual symptoms were prospectively confirmed (see
Chapter 10). These data, therefore, failed to support
hypotheses of excesses or deficiencies of circulating
gonadal steroids (either progesterone or estradiol) in
PMDD. Indeed, both observational and controlled
studies also demonstrated that the symptoms of PMDD
could be dissociated from the endocrine events of the
luteal phase. Specifically, PMDD symptoms were observed despite blinded luteal phase function, including
during luteal phase truncation with high doses of the
progesterone receptor antagonist RU-4861 as well as
during luteal phase administration of low doses of RU486.2 Thus, the symptoms of PMDD could occur in the
absence of the endocrine events of a normal luteal
phase.
These data then raised the next question of whether
reproductive-endocrine events occurring prior to the
luteal phase might nonetheless be influencing subsequent symptom development. To test this possibility,
several studies examined the effects on PMDD of either
ovarian suppression with gonadotropin-releasing
hormone (GnRH) agonists (under placebo-controlled
conditions) or oophorectomy (during unblinded observational follow-up) in women with prospectively confirmed PMDD. The findings of these studies consistently
documented that the elimination of cyclic ovarian
activity reduced both symptom severity and cyclicity in
the majority of women with PMDD (see Chapter 10).

Two studies pursued these observations further and
examined the effects of administering physiological
doses of ovarian steroids to those women whose
PMDD was in remission during ovarian suppression3
or postoophorectomy,4 respectively. In the approximately 60% of women whose PMDD symptoms were
significantly attenuated or eliminated by ovarian suppression, symptoms returned within 2 weeks of initiating
replacement of estradiol or progesterone to physiological levels, and remitted by the fourth week of administration. In contrast, in the study by Schmidt et al,3 in
the group of control women lacking a history of PMDD,
neither the hypogonadal nor the hormone replacement
conditions were associated with any perturbation of
mood. Consistent with the findings from basal hormone
studies, then, it appears that PMDD represents an
abnormal response to normal hormone changes or
levels rather than a ‘normal’ response to a hormonal
abnormality.
Ovarian suppression is effective in approximately
60% of women with PMDD, and in these women physiological levels of estradiol and/or progesterone trigger
a recurrence of PMDD symptoms; nonetheless, we
cannot infer a simple relationship between PMDD and
ovarian hormone secretion. For example, in these same
studies many women with otherwise identical forms of
PMDD continued to experience cyclic symptoms despite hormonal evidence of adequate ovarian suppression. Thus, a considerable proportion (i.e. 20–40%) of
women with PMDD show a ‘hormone-independent’
condition, since PMDD symptoms did not improve
with ovarian suppression. Additionally, GnRH agonists
also suppress ovarian androgen production, which contributes approximately 50% of circulating androgens
in women. Thus, the ability of GnRH agonists (with or
without estradiol and progesterone) to regulate symptom expression must be interpreted in the context of
accompanying relative hypoandrogenism.
These caveats notwithstanding, in the women with
PMDD whose symptoms are eliminated by ovarian
suppression, changes in estradiol or progesterone secretion ‘trigger’ the onset of symptoms. Our studies, then,
raised several questions:
1.

2.

3.

Why do similar changes in, or levels of, gonadal
steroids trigger mood deterioration in women with
PMDD while showing no apparent effect on mood
in women lacking this history?
Is it the rate of change in the hormone level or the
exceeding of a critical threshold that results in the
triggering effect?
Will continued exposure to stable levels of gonadal
steroids be associated with the continuation, disappearance, or episodic recurrence of mood symptoms?

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NATURE OF HORMONAL TRIGGER
The ability of ovarian steroids to precipitate mood
symptoms in women with PMDD could reflect either a
change in gonadal steroid levels or the exceeding of a
critical threshold of hormone secretion above which
cyclic symptoms are manifest. We initiated a study in
which we continuously administer hormone replacement for 3 months in women with PMDD in whom we
document that ovarian suppression eliminates symptom
severity and cyclicity. Women with PMDD receive
Lupron (leuprolide; 3.75 mg IM every month) for 6
months. After month 2, those women showing elimination of PMDD symptoms receive placebo for 1 month
(to identify placebo-related symptom induction). Those
women not showing symptoms on placebo during the
third month then receive estradiol (Estraderm patch
100 ␮g every day) and progesterone (200 mg suppository twice a day) for the next 3 months. We reasoned
that if the symptoms recurred monthly, it would suggest
that the change in steroid levels is of no consequence (as
no change occurs after the first month) and it is the level
of gonadal steroids that is relevant and necessary but
not sufficient (i.e. there must occur some other cyclical
process [e.g. an infradian rhythm that is ovarian steroiddependent] that allows for the precipitation and remission of symptoms while constant gonadal steroid levels
are maintained). If subjects were symptomatic during
the first month and then experienced no recurrence of
symptoms during the next 2 months, it would rule out
the importance of the level of gonadal steroids per se
(even in the presence of an infradian factor) as the precipitant of symptoms. To date, preliminary data suggest
that the change in gonadal steroids triggers mood
destabilization, with no further symptomatic episodes
recurring over the subsequent 3 months.5 These data
do not permit us to identify whether it is the change in
progesterone or the change in estradiol that is the triggering stimulus. Future studies employing either selective estrogen and progesterone receptor antagonists or
the selective withdrawal of estrogen and progesterone
could dissect out the roles of estrogen and/or progesterone as the steroid signal in PMDD. Finally, these
preliminary data suggest that continuously (rather than
sequentially) administered oral contraceptives might
successfully treat PMDD, a significant potential advance
in the available therapeutic options.6,7

and behavioral symptoms without further consideration of how changes in the brain could mediate these
symptoms other than through vague reference to
‘disturbances of neurotransmitters’. Such a conception
both ignores the phenomenology of the symptomatic
state in women with PMDD8,9 and fails to incorporate
recent discoveries in affective neuroscience. Clinical
observations in women with PMDD suggest that the
neurocircuitry targeted by ovarian steroids comprises
those brain regions implicated in the regulation of
affective state and the stress response, abnormalities of
which are also described in depression. Indeed, PMDD
shares many common features with traditional affective
disorders. First, the symptoms of PMDD are similar to
those of an atypical depression, e.g. sadness, anxiety,
carbohydrate craving, and hypersomnia. Additionally,
as part of this dysphoric state, women with PMDD
demonstrate negative affective bias and report anhedonia
(inability to enjoy otherwise pleasurable events), social
avoidance, and emotional overreaction to stressful situations along with other symptoms of affective maladaptation. Secondly, the prevalence of a past history
of major depression is substantially increased in women
with PMDD compared with the normal population.
Thirdly, some of the efficacious (e.g. SSRIs) or putatively
efficacious (sleep deprivation, phototherapy) treatments
for PMDD are also employed in the treatment of depression. Fourthly, some of the biological systems that are
‘dysregulated’ with increased frequency in women with
PMDD are the same systems that have shown increased
frequency of dysregulation in depression: e.g. blunted
or exaggerated adrenocorticotropic hormone (ACTH)
response to corticotropin-releasing hormone (CRH),
blunted or exaggerated thyroid-stimulating hormone
(TSH) response to thyrotropin-releasing hormone
(TRH), decreased serotonin peripheral binding and
uptake, and phase-shifted circadian rhythms.
Additionally, as suggested by Rubinow and Schmidt,10
PMDD comprises several other disturbances during the
luteal phase indicative of dysfunctions in specific brain
regions:
●

●
●

●
●

NATURE OF SUBSTRATE
While the obvious candidate for mediating PMDD
symptoms is the ‘central nervous system’, most studies
to date regard PMDD as an array of negative affects

Many of these processes are regulated by and reflect the
input of several interconnected brain regions (circuits),

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174 THE PREMENSTRUAL SYNDROMES

including the prefrontal cortex (PFC), orbitofrontal
cortex (OFC), anterior cingulate cortex (ACC), amygdala, striatum, and ventral tegmentum/nucleus accumbens. Excessive activation (e.g. amygdala activation) or
deficient activation (i.e. loss of inhibition from PFC or
OFC) of specific brain regions is associated with dysphoric states. For example, increased amygdala activation (or inappropriate amygdala activation) is associated
with prolonged negative mood states and with trait vulnerability to experience depression.13,14 The findings of
many investigators15–20 emphasize that symptoms of
affective dysregulation can be understood by studying
the activation patterns of interconnected and reciprocal
inhibitory brain regions (e.g. OFC and amygdala)
rather than in the activity of one specific brain region
acting in isolation. Deficient PFC activation, for
example, may result in unrestrained amygdala activation,17 with aforementioned negative impact on mood,
and in unrestrained stress-related dorsal raphe activation,21 with consequent amplification of the adverse
biological and behavioral effects of stress. Similarly,
interconnecting neurocircuits have been described
between the PFC and the locus coeruleus that could be
important for the regulation of arousal, focused attention, and performance during conflict or stress.22,23
While stimulated PFC and amygdala function have not
been examined in PMDD, deficits in the recognition of
facial emotion during the luteal phase in women with
PMDD12 is suggestive of abnormal amygdala function,
similar to observations in depressed subjects, of both
altered amygdala activation in response to masked
faces24 as well as deficits in facial emotion recognition.25 Women with PMDD but not controls showed
menstrual cycle-related variation in performance on the
Facial Discrimination Task (FDT), with both impaired
performance and prominent negative bias (e.g. identifying neutral faces as sad) seen during the luteal phase.
No menstrual cycle phase effect nor diagnostic effect
was seen on a control task. The bias in affective processing in women with PMDD is state-related
(although not correlated with symptom ratings) and
suggests that events related to the luteal phase may
trigger functional dysregulation in those brain regions
mediating the recognition of emotional facial expression (e.g. amygdala, OFC, fusiform gyrus, superior
temporal sulcus), brain regions that have also been
implicated in depression. Additionally, the bias in affect
assessment (the experience of stimuli as both more
emotional and more negative) in the luteal phase in
women with PMDD may contribute to the generation
and perpetuation of negative affective states. For
example, Hooker et al26 show that an inability to
perform reversal learning with emotionally charged
faces is associated with an oversensitivity to negative

social cues, cognitive inflexibility, and a differential
pattern of brain regional activation on functional magnetic resonance imaging (fMRI). Disturbances observed
in women with PMDD during the luteal phase may also
implicate other elements of the affective neurocircuitry.
The negative bias/affective misperception could reflect
the mis-assessment of emotional information seen with
dysfunction of the normal balance between dorsal and
ventral anterior cingulate cortical activity.27 The failure
to access positive mood states and to update frontal
representations, and the consequent maladaptive behavioral response selection, may suggest dysfunctional
reward circuitry, with impaired phasic mid-brain
dopaminergic modulation of prefrontal cortical activity.28 This possibility is enhanced by our observation of
decreased capacity for emotional reappraisal and
recovery in women with PMDD (Dancer et al, personal
communication). Studies by Schultz and colleagues29
demonstrate that a reward that is smaller than that
expected will actually inhibit the firing of dopamine
neurons associated with the expectation of the reward.
Thus, an affective misperception may contribute to as
well as reflect the experience of anhedonia or dysphoria.
If the actual physiological substrates (i.e. neurocircuits, neurotransmitters, and stress axis) implicated
in PMDD can be identified, then a critical question is
whether the functions of these systems are regulated
by ovarian steroids. Two strategies are employed to
answer this question: comparison of outcome measures
in the follicular and luteal phases of the menstrual
cycle; and comparison during GnRH agonist-induced
hypogonadism and hormone replacement.
Recent brain imaging studies in asymptomatic
women (i.e. women without PMDD) confirm for the
first time in humans that physiological levels of ovarian
steroids have the capacity to modulate the neurocircuitry thought to be involved in both normal and
pathological affective states. First, Berman et al performed cognition-activated 15O PET (positron emission
tomography) scans in women during conditions of
GnRH agonist-induced hypogonadism and gonadal
steroid replacement. They observed the elimination of
Wisconsin Card Sort-activated regional cerebral blood
flow (rCBF) in the dorsolateral prefrontal cortex as
well as an attenuation of cortical activation in the inferior parietal lobule and posterior inferior temporal
cortex (bilaterally) during GnRH agonist-induced
hypogonadism.30 The characteristic pattern of cortical
activation re-emerged during both estradiol and progesterone add-back. Additionally, they observed a differential pattern of hippocampal activation, with estradiol
increasing and progesterone decreasing activation relative to hypogonadism. This was the first demonstration
that ovarian steroids have activational effects on rCBF

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during cognitive stimulation in the brain regions (i.e.
PFC) implicated in disorders of affect and cognition.
Secondly, Goldstein et al31 observed an increase in
amygdala activity and arousal (as measured by fMRI
and skin conductance, respectively) during the late follicular phase of the menstrual cycle (higher estradiol
levels) compared with the early follicular phase (characterized by relatively low estradiol levels). Thirdly,
Protopopescu et al32 employed an affective pictures
task in an fMRI study and observed increased OFC
activity (a region that in some studies exerts inhibitory
control over amygdala functioning) during the luteal
compared with the follicular phase. Moreover, preliminary data from these same investigators in women with
PMDD (DC Silbersweig, pers comm) suggest a relative
loss of OFC activity (decreased inhibition) in women
with PMDD during the luteal phase. Notwithstanding
the caveat that decreased cortical ‘activity’ could also
reflect more efficient or optimal function, these data
suggest that a reduction in OFC inhibition of amygdala
function during the luteal phase is associated with
PMDD symptoms. Finally, Dreher et al33 performed an
event-related fMRI study of reward processing across
the menstrual cycle in women with PMDD and controls. The paradigm employed disentangles transient
reward error prediction (PFC) from sustained response
to reward uncertainty (ventral striatum). Preliminary
data in the controls demonstrate, for the first time in
humans, that ovarian steroids modulate reward system
function, with increased follicular phase activation of
the OFC and amygdala during reward anticipation and
of the midbrain, striatum, and left ventrolateral PFC
during reward delivery. New analytical approaches will
allow for testing the hypothesis that the hormonally
induced alteration in function includes changes in interregional neural interactions. These findings then
suggest that cognitive and affective information
processes may serve as probes to identify candidate circuits for the mediation of gonadal steroid-dependent
affective dysregulation. Additionally, neuroimaging
studies in women suggest that ovarian steroids can
influence many neural processes and systems relevant
to PMDD, including arousal, stress responsivity, and
reward processing.
The description of altered stress reactivity34–36
during the luteal phase in women with PMDD suggest
that the HPA axis might also be an important target for
ovarian steroids in women with PMDD. Although
we37,38 were unable to confirm reported (albeit inconsistent) differences between patients and controls in
basal plasma ␤-endorphin, ACTH, or cortisol, we did
find significant differences in stimulated HPA axis
activity.39,40 Consequently, we examined exercise stressstimulated levels of arginine vasopressin (AVP), ACTH,

and cortisol in PMDD patients and controls during
both the follicular and luteal phases of the menstrual
cycle. Women with PMDD failed to demonstrate the
luteal phase-enhanced HPA axis activation seen in the
controls.41 These data are of interest for several
reasons. First, the luteal phase-related enhancement of
stimulated HPA axis activity seen in the controls complements the observation that the HPA axis response is
significantly increased in the presence of progesterone
during GnRH agonist-induced ovarian suppression
(comparable to the luteal phase).41 Thus, not only is it
progesterone rather than estradiol that has the greater
impact on HPA axis activation in humans (unlike in
rodents) but also the HPA axis response to progesterone
appears to differ in women with PMDD and controls.
Thus, several physiological substrates that control
both affective and stress adaptation are also regulated
by gonadal steroids and, therefore, could be sites of the
differential response to the hormone signal in PMDD.
Future studies employing probes of these systems combined with multimodal brain imaging techniques will
better characterize and, possibly, confirm the relevance
of these substrates in PMDD.

GONADAL STEROID SIGNAL MODULATION:
ROLE OF CONTEXT
As more is learned about steroid–steroid receptor signaling, the possible sources of altered steroid signaling
in PMDD grow exponentially. Several observations in
women with PMDD must be incorporated into the
search for the contextual variables that differentially
modulate steroid signaling in PMDD. First, the actions
of ovarian steroids at non-CNS sites appear to be
normal in women with PMDD and, therefore, the differential steroid signal is substrate/tissue specific. Thus,
women with PMDD could have a differential metabolism of steroids, resulting in locally (i.e. within specific
regions of the CNS) increased or decreased tissue levels
of steroids or their metabolites. Secondly, PMDD
demonstrates a high rate of heritability, suggesting genotypic variation may contribute to altered (and tissuespecific) steroid signaling. Finally, symptoms develop
over the course of reproductive life in those women
with PMDD, suggesting either behavioral sensitization
or possible epigenetic modification of steroid signaling
pathways, perhaps by interaction with other contextual
variables such as early-life trauma, reproductive aging, or
the occurrence of episodes of major/minor depressions
(both reproductive and non-reproductive-related).
Whereas mood disorders may be seen in association with
the pathological function of certain endocrine organs
(e.g. adrenal, thyroid), mood disturbances precipitated

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by gonadal steroids in PMDD appear in the context of
normal ovarian function. Thus, although substrates
such as OFC/PFC–anterior cingulate–amygdala neurocircuits, the serotonergic system, and HPA axis can be
identified as potential targets for the ovarian steroid
signal, studies must examine means by which otherwise
normal steroid signals elicit a change in behavioral
state.
The neurosteroid metabolites of progesterone (and
androgens) are of considerable interest as possible
mediators of the behavioral effects of gonadal steroids
in PMDD (see Chapter 10). Whereas reports of altered
allopregnanolone levels in PMDD are inconsistent,
several findings suggest the relevance of neurosteroids
in PMDD, including the following:
●

●

●

allopregnanolone plasma levels have been correlated with PMDD symptoms
altered sensitivity to benzodiazepines/neurosteroids
has been found in women with PMDD
women with PMDD fail to show the normal luteal
phase-related blunting of cortical activation presumed to be due to allopregnanolone.42

Although we previously reported no differences in
luteal phase allopregnanolone and pregnanolone levels
in women with PMDD compared with controls,43
studies during GnRH agonist-induced ovarian suppression enabled us to examine the metabolism of progesterone during constant daily dosing and without the
confound of variable ovarian progesterone production.
In preliminary data, women with PMDD differed from
controls, showing a greater decrease for peak allopregnanolone and 5␣-dihydroprogesterone (DHP) levels
(PMDD). Further, in women with PMDD, evidence of
decreased 5␣-reductase activity (decreased DHP) and
3␣-hydroxysteroid oxidoreductase (3␣-HSD) activity
(decreased allopregnanolone) correlated with symptom
ratings. These findings suggest that differences in the
activity of the synthetic (or metabolic) enzymes for neurosteroids (or differences in metabolite conversion,
sequestration, or clearance) might translate into phenotypic differences. This possibility is strengthened by
observations that different metabolites of progesterone
have opposite central neuromodulatory effects (e.g.
3␣-metabolites are GABAA receptor agonists, whereas
3␤-metabolites are GABAA antagonists)44 and changes
in reproductive hormones are known to modulate
5␣-reductase activity in the amygdala of non-human
primates.45
In collaboration with Dr Synthia Mellon, we have been
measuring the activity of one of the two major enzymes
responsible for the production of allopregnanolone
(3␣-HSD) in women with PMDD to determine whether

lower activity of this enzyme might account for both
gonadal steroid-triggered symptoms (due to low allopregnanolone levels and elevated dihydrotestosterone
(DHT) levels) and responsivity to SSRIs (which stimulate the activity of the enzyme). While initial efforts
have been primarily directed at determining the effect
of menstrual cycle phase on enzyme activity in controls,
preliminary data suggest that women with PMDD may
have (paradoxically) increased conversion of DHP to
allopregnanolone compared with controls (Rubinow et
al, pers comm). Additionally, women with PMDD have
increased levels of lymphocyte 3␣-HSD mRNA but no
differences in 5␣-reductase mRNA levels.
Allopregnanolone is also a positive modulator of the
GABAA receptor. Animal study data from several laboratories46–48 demonstrate that both chronic (3–5 days)
exposure to and subsequent withdrawal from progesterone or allopregnanolone alter the expression of
GABAA subunits (and the composition of the receptor)
in such a way as to greatly diminish both the sensitivity
to benzodiazepine potentiation and the agonist response
of the GABAA receptor/chloride ion channel. Blockade
of the formation of allopregnanolone with either 5␣reductase inhibitors (finasteride) or 3␣-HSD inhibitors
(indomethacin) prevented the adverse behavioral
effects (irritability and withdrawal-like symptoms) seen
following progesterone exposure in rats.49,50 Thus, the
blockade of allopregnanolone-induced alterations in
GABAA receptor activity might similarly prevent progesterone/luteal phase-related symptom appearance in
women with PMDD. Given the toxicity of indomethacin and the lack of efficacy of finasteride against type I
5␣-reductase (the isoform present in the brain), this
hypothesis could be tested only recently with the development of dutasteride, which antagonizes type I
5␣-reductase.
Finally, as metabolomic techniques develop, investigators will have the ability to more directly examine the
products of cellular metabolism. The advantages of
metabolic profiling are compelling and described elsewhere.65 The estimated number of human cellular
metabolites is several orders of magnitude smaller than
the numbers of genes, transcripts, or proteins. Further,
metabolomic technology permits inferences about
disturbances in metabolic pathways. For example, if
5␣-reductase activity is altered in women with PMDD,
as suggested to be the case in polycystic ovary syndrome
(increased),51 one would expect an array of changes in
metabolic profile, including changes in allopregnanolone,
5␣-dihydroprogesterone,
dihydrotestosterone, and progesterone concentrations. Thus,
potential alterations in neurosteroid metabolism should
be more comprehensively demonstrated with this technique, because the extended metabolic pathway of

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a substance/enzyme is being measured. These studies
may enable investigators to determine both the metabolic consequences of ovarian steroid exposure, as well
as the identity of candidate mediators of the differential
behavioral response (i.e. altered pattern of metabolites)
observed in women with PMDD.
A second possible site of differential steroid signal
modification is at the level of the steroid receptor.
Steroid receptor function is modified by an array of
tissue-specific factors including the relative concentration of co-regulator proteins, the presence and activity
of receptors for other members of the steroid family or
receptor subtypes, and concurrent action of the steroid
at the cell membrane. In human disease one of the best
characterized sources of variation in steroid receptor
function is genomic. Polymorphisms in gonadal steroid
receptors have been shown to alter receptor transcriptional efficacy (e.g. CAG repeat in exon 1 of the androgen
receptor; progins insertion in intron 7 of the progesterone receptor; T1057G in exon 5 of ␤-estrogen receptor) and to be associated with differential illness risk
(i.e. prostate cancer, breast cancer).52–55 Additionally,
the susceptibility to the disruptive effects of estradiol
on reproductive development differs enormously (up to
100-fold) between mouse strains, with the genotype
contributing more to the variance than the dose of
estradiol employed.56 Finally, a single nucleotide polymorphism enables progesterone to activate a receptor,
the mineralocorticoid receptor, at which it normally
functions only as a competitive inhibitor, thus providing
a means by which normal steroid levels create a different
phenotype (hypertension).57 There is precedent, then,
for expecting that polymorphisms in the gonadal steroid
signaling pathway or in gonadal steroid-regulated genes
could alter the nature or strength of the steroid signal
as well as phenotype. Alternatively, non-steroid-related
genes could be implicated in the vulnerability to develop
the differential behavioral response to ovarian steroids
in PMDD. For example, Caspi et al58 demonstrated
that the risk of developing depression is predicted by
the experience of stressful life events in combination
with a specific genetic background but is not predicted
by either the genetic or environmental factors when
considered separately. Thus gene–environment interactions represent a promising explanation for the differential behavioral sensitivity to gonadal steroids seen in
women with PMDD. Analogous to the suggestion by
Caspi et al, PMDD symptoms could develop after a
hormonal stimulus (i.e. the environmental event)
against the background of a specific genetic context.
Whereas some earlier candidate gene studies did not
find significant associations with PMDD,59 we have
recently identified a region of the ESR1 gene containing
multiple polymorphic alleles that associate with PMDD,

thus lending support to the idea that the effects of multiple genes may interact in creating a dysphoric behavioral response to normal gonadal steroid levels.64
The contributions of genotypic variation to PMDD
phenotype could be modified by several other factors,
including both epigenetic processes as well as gene–
environment or gene–steroid interactions. For
example, Meaney et al60,61 have demonstrated that the
behavioral phenotype can be determined by environment-induced alterations in the expression of the
genome. Thus, early-life trauma or past episodes of
depression, both frequent accompaniments of
PMDD,62 could potentially modify the substrate
response to the gonadal steroid trigger. As more is
learned about both the nature of gonadal steroid
signaling in the brain and the complexities of gonadal
steroid-regulated behaviors, the sources of the differential response to gonadal steroids in PMDD will be
clarified. In summary, women with PMDD could have
excessive or deficient gonadal steroid signaling that
might alter the processing of stressors and lead to a
dysregulated affective response63 or altered learning
that could favor the development of behavioral sensitization or steroid-dependent interoceptive cueing of
behavioral states.

CONCLUSIONS
In PMDD there is a well-defined endocrine stimulus
that for many women with this condition is critical in
the precipitation of affective state disturbances. This
affords a unique opportunity to identify neural substrates involved in the regulation of the affective state
that could be targeted in the development of novel
treatment strategies. Our pursuits of several testable
hypotheses in PMDD will advance our understanding
of this disorder, illuminate mechanisms by which reproductive steroids may regulate the affective state, and
help identify the locus of the differential sensitivity that
permits reproductive steroids to destabilize mood in
some but not all women. A better understanding of the
pathophysiology of this complex disorder will permit the
development of theoretically driven treatment strategies and, hopefully, predictors of therapeutic response
for the considerable number of women with PMDD
who are not responsive to either ovarian suppression
strategies or SSRIs.

ACKNOWLEDGMENT
The research was supported by the Intramural Research
Programs of the NIMH.